Whey Infant Formula

In 1919, Gerstenberger and Ruh [1] developed the first commercially available formula with cow's milk as the exclusive source of proteins. The original protein content of the manufactured formula was 1.8g/100kcal, but was increased to 2.2g/100kcal in 1945 [2]. In the middle of the 20th century, it was considered that formula-fed (FF) infants require a considerably greater intake of protein than breast-fed (BF) infants. This recommendation was based on an overestimation of both the nutritionally available protein content of human milk and the protein intake requirements of the infants [3, 4]. Furthermore, cow's milk protein quality and digestibility was considered far inferior to that of human milk for satisfying the amino acid needs of infants. In the 1960s, the protein content of a number of widely used formulas ranged from 3.3 to 4.0g/100kcal and some formulas, designed for managing diarrhea, even provided up to 6.7g/100kcal [5]. Subsequently, national health institutes and pediatric associations defined standards for protein content in infant formulas (table 1). While there is now a consensus for the minimum required values (1.8g protein/100 kcal), a broader range of recommended maximum values can be found (2.8-4.5g protein/100 kcal). In 1991, a European Directive set the maximum protein content to 3.0g/100kcal. However, the Food and Drug Administration still recommended a maximum required intake level of 4.5 g/100 kcal, in spite of the revisions proposed by a task force of the American Academy of Pediatrics [5]. A current revision of the Codex proposes a maximum protein content of 3.0g/100kcal, for both starter and follow-on formulas, based on new recommendations from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (table 1).

The intrinsic superiority of human milk protein over that of cow's milk is due to its higher whey to casein protein ratio (approximately 60:40 in human milk and 20:80 in bovine milk). In 1961, a major technological breakthrough (i.e. demineralization of whey protein through an electrodialysis process) allowed the addition of equal parts of casein and whey in formula, and by the mid 1990s, whey-predominant formulas prevailed in the US and Europe. Nevertheless, both the whey and casein fractions of cow's milk are quite different from those of human milk (fig. 1). Consequently, the amount of amino acids delivered by breast milk and formula differ. Compared to breast milk, the levels of most of the essential amino acids are, per gram of protein (or nitrogen), lower in the casein-predominant formulas, while leucine, pheny-lalanine, tryptophan, and to a lesser extent valine, are limited in whey-predominant formulas (fig. 2). In order to compensate for these quantitative differences, the amount of proteins per energy content must be higher in formula than in human milk. A casein- or a whey-predominant formula containing 2.5 g protein/100 kcal, provides, an excess of most of the essential amino acids found in breast milk. Nevertheless, tryptophan and the conditionally essential amino acid cystine are limiting factors for further reducing the protein quantity in cow's milk formula (fig. 3). Indeed, Janas et al. [6] demonstrated that term infants fed formulas with reduced protein content (1.8g/100kcal) and various whey/casein ratios had normal plasma cystine levels but depressed levels of tryptophan when compared to those fed human milk. New approaches/processes were therefore needed to adjust the protein/energy ratio to the minimal recommended value (1.8 g/100 kcal) and, thereafter, to that more closely resembling human milk.

In principle, the easiest way to avoid lower plasma levels of tryptophan in FF infants is to supplement the formula with free tryptophan. In 1992, studies demonstrated that term infants, fed a casein-predominant formula, reduced in protein (1.9-2.0g/100kcal) but fortified in free tryptophan, had similar plasma tryptophan levels to BF infants [7, 8]. However, taking into account the absorption kinetics of free and protein-bound tryptophan, as well as toxi-cological and economical considerations, supplementing with free tryptophan is not the most favorable option. Addition of a-lactalbumin (aLA) may provide a promising alternative [9]. The aLA fraction is rich in tryptophan (5.9%) but the proportion of aLA in bovine milk (4%) is considerably lower than in human milk (28%; fig. 1). Whey protein concentrates, or isolates enriched in aLA and produced by either ion exchange or membrane fractionation, became commercially available in the late 1990s [10]. The effect of aLA enrichment on tryptophan supply has been studied in healthy term infants fed a whey-predominant formula containing 2.0 g protein/100 kcal and 2.2 g tryptophan/16 g N over a 2-week period [11]. It was demonstrated that the









Proteose peptone


Serum albumin





Fig. 1. Protein composition of human and cow's milk. Adapted from Heine et al. [9].

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