German Infant Nutritional Intervention Study Research Articles

Partially Hydrolyzed Whey Protein: A Review of Current Evidence, Implementation, and Further Directions

Background: Human milk is known to be the best nutrition for infants as it provides many health benefits. For non-breastfed infants, cow's milk based infant formula is the most optimal option to provide the needed nutrition. However, approximately 2-5% of all formula-fed infants experience cow’s milk allergy during their first year of life. Partially hydrolyzed whey formula (pHF-W) have been widely recommended to prevent the development of allergic disease in infants. However, according to epidemiological data, approximately half of the infants developing allergy are not part of the at-risk group.Objectives and Methods: This article aims to review the effects of pHF-W in preventing allergy, especially atopic disease, in all non-breastfed infants, as well as the safety aspect of pHF-W if used as routine formula. The role of pHF-W in the management of functional gastro-intestinal (GI) disorders is also reviewed.Results: Several clinical studies showed that pHF-W decrease the number of infants with eczema. The strongest evidence is provided by the 15-year follow up of the German Infant Nutritional Intervention study which showed reduction in the cumulative incidence of eczema and allergic rhinitis in pHF-W (OR 0.75, 95% CI 0.59-0.96 for eczema; OR 0.67, 95% CI 0.47-0.95 for allergic rhinitis) and casein extensively hydrolysed formula group (OR 0.60, 95% CI 0.46-0.77 for eczema; OR 0.59, 95% CI 0.41-0.84 for allergic rhinitis), compared to CMF as a control, after 15 years of follow-up. pHF-W was also found to be beneficial in the management of functional GI disorders such as regurgitation, constipation and colic.Conclusions: The use of pHF-W in allergic infants has been recommended in various guidelines across the countries, as a primary prevention of allergic disease. One pHF-W has been approved by the US FDA and the European Commission's European Food Safety Authority (EFSA) for its safety and suitability as a routine infant formula for all healthy infants. According to the data obtained in the management of functional GI disorders, pHF-W is better tolerated than formula with intact protein. Further studies assessing the effect of routine use of pHF-W in a larger population of non-breastfed infants should also be conducted, in order to observe any potential harm and to determine the benefit and cost-effectiveness ratio.

The German Infant Nutritional Intervention Study (GINI) for the preventive effect of hydrolysed infant formulas in infants at high risk for allergic diseases. Design and selected results

In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow’s milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention-Program (GINI) was supported for the first 3 years by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomized, double-blind intervention study was to investigate the impact of different cow’s milk protein hydrolysate infant formulas in the first 4 – 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow’s milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children’s Department, Ludwigs-Maximilians-University Munich and Children’s Department Technical University Munich) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow’s milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow’s milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow’s milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow’s milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomization to standard cow’s milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions.

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

The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. 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 cow's milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. 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 cow's 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. 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.

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

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. 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. 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. Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain.

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.

A new FFQ designed to measure the intake of fatty acids and antioxidants in children

The present paper describes the systematic development of an FFQ to assess the intake of fatty acids and antioxidants in school-aged children. In addition, a validation study applying 24 h dietary recalls was performed. Using the variance-based Max_r method, a list of eighty-two foods was compiled from data obtained by 3 d weighed dietary records. The foods were used to design an FFQ, the comprehensibility of which was evaluated in a feasibility study. In addition, the FFQ was validated in a subset of 101 children from the German Infant Nutritional Intervention Study (GINI PLUS) against one 24 h dietary recall. The feasibility study attested a good acceptance of the FFQ. Mean intake of foods compared well between the FFQ and the 24 h dietary recall, although intake data generated from the FFQ tended to be higher. This difference became less apparent at the nutrient level, although the estimated average consumption of arachidonic acid and EPA using the FFQ still exceeded values recorded with the 24 h recall method by 45 % and 29 %, respectively. On the basis of the systematic selection process of the food list, the established practicability of the FFQ and the overall plausibility of the results, the use of this FFQ is justified in future epidemiological studies.

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

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

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

The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. 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 cow's milk formula (CMF) in a randomized, double-blind trial. 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. In the intent-to-treat analysis the relative risk of a physician's 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. The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.

Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: Three-year results of the German Infant Nutritional Intervention Study

Recommendations for primary prevention of allergic diseases in high-risk children include feeding with hydrolyzed formulas if breast-feeding is insufficient. The primary objective of the German Infant Nutritional Intervention study was to investigate the allergy preventive effect of 3 hydrolyzed formulas compared with cow's milk formula in the first 3 years of life in a randomized, double-blind trial. Between 1995 and 1998, 2252 newborns with atopic heredity were allocated to a group receiving cow's milk formula, partially or extensively hydrolyzed whey formula, or extensively hydrolyzed casein formula as a milk substitute for the first 4 months if breast-feeding was insufficient. Main outcome parameters were allergic manifestations, atopic dermatitis (AD), and asthma. After 3 years, 396 of 2252 children (17.6%) had dropped out. Breast-fed infants without formula feeding during the intervention (n = 889) were considered separately. A significant reduction of the incidence of AD was achieved with the extensively hydrolyzed casein formula in the intention-to-treat (ITT; n = 1363) and per protocol (PP; n = 904) analyses (ITT: population odds ratio [95% CI], 0.67 [0.45-0.99]; PP: adjusted odds ratio [OR(adj)], 0.53 [0.32-0.88]), and with the partially hydrolyzed whey formula in the PP analysis (ITT: population odds ratio, 0.76 [0.52-1.11]; PP:OR(adj), 0.60 [0.37-0.97]). None of the formulas reduced the incidence of asthma. The risk for AD, but not for asthma, can be reduced with certain cow's milk hydrolyzates in high-risk infants when breast-feeding is insufficient. Early nutritional intervention in high-risk children has significant influence on the incidence of AD, but not of asthma.

Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children

Objectives: To estimate long-term exposure to traffic-related air pollutants on an individual basis and to assess adverse health effects using a combination of air pollution measurement data, data from geographical...

Reply

Reply

Dietary prevention of allergy, atopy, and allergic diseases

Dietary prevention of allergy, atopy, and allergic diseases

The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: The German Infant Nutritional Intervention Study, a randomized double-blind trial

Background: The potential of extensively or partially hydrolyzed formulas to reduce the risks for allergies is controversial. Objective: We sought to assess the preventive effect of differently hydrolyzed formulas compared with cow's milk formula (CMF) in high-risk infants. Methods: Between 1995 and 1998, 2252 infants with a hereditary risk for atopy were enrolled in the German Infant Nutritional Intervention Study and randomly assigned at birth to one of 4 blinded formulas: CMF, partially hydrolyzed whey formula, extensively hydrolyzed whey formula, and extensively hydrolyzed casein formula (eHF-C). The primary end point at 1 year of age was the presence of allergic manifestation, which was defined as atopic dermatitis (AD), gastrointestinal manifestation of food allergy, allergic urticaria, or a combination of these factors. Results: At 12 months per protocol, analysis was performed on 945 infants exposed to study formula: 304 (13.5%) infants had left the study, 138 (6.1%) infants were excluded because of noncompliance, and 865 infants were exclusively breast-fed the first 4 months of life. The incidence of allergic manifestation was significantly reduced by using eHF-C compared with CMF (9% vs 16%; adjusted OR, 0.51; 95% CI, 0.28-0.92), and the incidence of AD was significantly reduced by using eHF-C (OR, 0.42; 95% CI, 0.22-0.79) and partially hydrolyzed whey formula (OR, 0.56; 95% CI, 0.32-0.99). Family history of AD was a significant risk factor and modified the preventive effect of the hydrolysates. Conclusions: Prevention of allergic diseases in the first year of life is feasible by means of dietary intervention but influenced by family history of AD. The preventive effect of each hydrolyzed formula needs to be clinically evaluated. (J Allergy Clin Immunol 2003;111:533-40.)