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Institute of Medicine (US) Committee on the Evaluation of the Addition of Ingredients New to Infant Formula. Infant Formula: Evaluating the Safety of New Ingredients. Washington (DC): National Academies Press (US); 2004.

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Infant Formula: Evaluating the Safety of New Ingredients.

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3Comparing Infant Formulas with Human Milk


The vast majority of infants in the United States are fed human-milk substitutes by 6 months of age. This food source, although inferior to human milk in multiple respects, promotes more efficient growth, development, and nutrient balance than commercially available cow milk.

Manufacturers often add new ingredients to infant formulas in an attempt to mimic the composition or performance of human milk. However the addition of these ingredients is not without risks as a result of a range of complex issues, such as bioavailability, the potential for toxicity, and the practice of feeding formula and human milk within the same feeding or on the same day.

Assessing the safety of ingredients new to infant formulas by comparing the proposed formulas with human milk also presents both regulatory and research issues. From a research standpoint, clinical studies that assess the effects of new ingredients are difficult to design because infants cannot be randomized to consume formulas or human milk. Furthermore, there may be significant non-nutritional confounding variables between the groups, including factors related to which mothers choose to breastfeed. Finally, human-milk composition varies considerably among and within individuals over time, while the content of infant formulas generally remains constant.

From a regulatory standpoint, the effect of an ingredient new to infant formulas is usually driven by the manufacturer's desire to produce a product that mimics the advantages of breastfeeding. This motivation implies that formulas in their current state are less efficacious (e.g., neurologically or immunologically), although not necessarily unsafe, when compared with human milk. Thus the safety of any addition of an ingredient new to infant formulas will need to be judged against two controls: the previous iteration of the formulas without the added ingredient and human milk.


Multiple health organizations, including the World Health Organization (WHO, 2002), the American Academy of Pediatrics (AAP, 1997), the American Academy of Family Physicians (AAFP, 2003), the American Dietetic Association (ADA, 2001), the Institute of Medicine (IOM, 1991), the Life Sciences Research Organization (LSRO, 1998), the U.S. Department of Health and Human Services (HHS/OWH, 2000), Health Canada, and the Canadian Pediatric Society (Canadian Paediatric Society, 1998) endorse breastfeeding as the optimal form of nutrition for infants for the first year of life. Nevertheless the vast majority of infants in the United States are fed human milk substitutes by 6 months of age (Ryan et al., 2002). This food source, although inferior to human milk in multiple respects, promotes more efficient growth, development, and nutrient balance than commercially available cow milk. The American Academy of Pediatrics recommends that infants who are not breastfed should consume iron-fortified infant formulas rather than cow or goat milk until 12 months of age (AAP, 1997).


Milk-Based Formulas

Human-milk substitutes existed before the modern age of formulas. Because some infants could not be fed by their mothers, humans adopted two methods for substitute feedings. The most obvious was the utilization of a surrogate mother (e.g., wet nurse), who would feed the child human milk. The alternative was to feed the child milk obtained from another mammal. The most frequently used sources were the cow, sheep, and goat (Fomon, 1993). Until the end of the nineteenth century, the use of a wet nurse was by far the safest way to feed infants who could not be breastfed by their mothers. As general sanitation measures improved during the latter part of the nineteenth century, and as differences in composition between human milk and that of other mammals were defined, feeding animal milk became more successful. However few infants survived until infant formulas based on cow milk with added water and carbohydrate were introduced. Box 3-1 lists the main landmarks in the history of the development of infant formulas. Liebig's food for infants was marketed in 1867 and consisted of wheat flour, cow milk, malt flour, and potassium bicarbonate (Fomon, 2001). In 1915 a formula called “synthetic milk adapted” was developed with nonfat cow milk, lactose, oleo oils, and vegetable oils. This was the basis for modern commercially prepared formulas (Fomon, 1993).

Box Icon

BOX 3-1

History of Commercially Available Infant Formulas in the United States. Cow-milk-based formulas 1867 – Formula contained wheat flour, cow milk, malt flour, and potassium bicarbonate

The limitations of using nonhuman-mammalian milks as substitutes became clear. As early as 1545, people were concerned with the feeding of animal milks to babies. The Boke of Chyldren stated that “If children be fed the milk of sheep, then their hair will be soft as that of a lamb, but if they be fed the milk of the goat, the hair will be coarse” (Phaire, 1955, P. 18). There are, of course, far greater concerns about feeding animal milk to infants, such as folate deficiency (goat milk) and early onset hypocalcemic seizures and azotemia (cow milk).

By the early twentieth century it was clear that cow milk was most likely the best animal-milk base to work from, but that certain modifications were needed to make it safe and palatable for human infants. These modifications included:

  • removing animal fat and substituting vegetable oils,
  • diluting the protein content for the newborn's relatively immature renal tubular system, and
  • adding or balancing minerals and vitamins (e.g., adding iron, adjusting the calcium: phosphorus ratio).

The process of modifying cow milk for large-scale production in the 1920s represented the birth of the infant formula industry. Since then new ingredients have been added for a variety of reasons. For example, iron was added in 1959 to reduce the risk of iron deficiency in formula-fed infants (Fomon, 1993), and long-chain polyunsaturated fatty acids (LC-PUFAs) were recently added in an effort to improve infant visual and cognitive development.

The protein content of formulas was a consideration from about 1935 onward. Early estimates of human-milk protein levels were higher than is now known, and it was believed that cow-milk protein was far inferior to human-milk protein. Formulas thus included high levels of protein (3.3–4.0 g/100 kcal). In the 1960s renal solute load began to be considered in the design of infant formulas, although infant formula regulations permit higher loads than are currently recommended by expert panels (no greater than 30 mosm/100 kcal) (Fomon, 2001).

Based on the recognition that human milk contains a predominance of whey proteins, while in cow milk, caseins are higher, formulas with a whey:casein ratio similar to human milk were introduced in 1962. By 2000 whey-predominant formulas were the most widely used milk-based formulas. These changes were made primarily based on composition rather than on functional measures (Fomon, 2001).

In 1984 taurine was added to infant formulas, based on at least a decade of studies that included composition, provisional essentiality, safety, and function in mammals (MacLean and Benson, 1989). Nucleotides were added to formulas with both compositional and efficacy claims in the late 1990s. They may act as growth factors and may have immunomodulating effects on immune defenses (Carver et al., 1991).

When considering new ingredients, manufacturers analyze every step in the production process, including raw materials (availability, source, and purity), processing methods, packaging, storage conditions and shelf life, methods of home preparation, and potential for misuse. Chapter 4 provides a discussion of these manufacturing considerations and their relevance to the regulatory process.

These considerations continue today as manufacturers attempt to alter infant formulas to imitate human milk in either composition or performance and to address the nutritional needs of specific infant populations (e.g., those with cow-milk allergy, metabolic abnormalities, and prematurity) (Benson and Masor, 1994). This chapter is concerned with infant formulas that are being altered to mimic composition or performance of human milk; it does not address the nutritional needs of specific infant populations.

Nonmilk-Based Formulas

Soy-based formulas were developed for infants perceived to be intolerant of cow-milk protein. The first soy formulas were commercially available in 1929 (Abt, 1965). These formulas were made with soy flour and were not well accepted by parents, who complained of loose, malodorous stools, diaper rash, and stained clothing. In the mid-1960s isolated soy protein was introduced into formulas. These formulas were much more like milk-based formulas in appearance and acceptance. However the preparation of isolated soy protein resulted in the elimination of most of the vitamin K in the soy, and a few cases of vitamin K deficiency were reported. The occurrence of nutrient deficiencies in infants fed milk-free formulas contributed to the development of federal regulations concerning the nutrient content of formulas (Fomon, 1993). Soy formulas now account for about 40 percent of formula sales in the United States. Some parents want to avoid cow-milk protein in the diet and thus wean directly to soy without any reported intolerance to cow-milk formulas. While formulas containing extensively hydrolyzed protein have long been available for infants with allergy to intact cow-milk protein, formulas with protein that is not as completely hydrolyzed have recently been introduced for normal-term infants.


Infant formula manufacturers have made changes to formulas in order to match either human milk composition or breastfeeding performance (Benson and Masor, 1994). The term “breastfeeding performance” is used because, with the exception of one study of preterm infants (Lucas et al., 1994), all other studies comparing human milk with formulas involved breastfeeding—not providing human milk from a bottle.

Matching Human-Milk Composition

Historically one approach to match human-milk composition is to add new ingredients (see Appendix B for the composition of formulas and human milk). This turns out to be a quixotic quest since human milk is a complex body fluid that is variable not only among individuals, but within an individual over time. In addition, it contains components, such as live cells and bioactive compounds, that either cannot be added to formulas or cannot survive a shelf life. Finally, not all human-milk constituents are essential; some, like LC-PUFAs, docosahexaenoic acid (DHA), and arachidonic acid (ARA), can be synthesized by term and preterm infants born at 33 weeks gestation (Uauy et al., 2000).

Manufacturers who wish to add some, but not all, ingredients found in human milk may defeat the purpose of the added nutrients or may potentiate negative interactions. Examples include the deleterious effect on growth when eicosapentaenoic acid is added without adequate DHA (Carlson et al., 1996) and the potential negative effect of adding polyunsaturated fats and large amounts of iron without adding adequate antioxidants (Halliwell and Chirico, 1993; McCord, 1996).

The issue of the context or matrix in which nutrients are provided in milk remains a challenge to infant formula manufacturers as they try to match human-milk composition and breastfeeding performance (Benson and Masor, 1994). The matrix can highly influence the bioavailability of nutrients. In the simplest example, nutrients that are present in both milks may be present in different ratios. For many nutrients that do not interact chemically or compete for enzymatic or receptor binding sites, the relative amounts may not be important. However in situations where there is competition for enzymes (e.g., among n-3 and n-6 PUFAs) (Brenner, 1974) or receptor binding sites in the intestine (e.g., for zinc, iron, and copper), the relative proportions may have biological significance.

Manufacturers must also consider the form of the molecule in which a nutrient is presented to the intestine and its bioavailability. For example, the high bioavailability of iron from lactoferrin in human milk allows for a much lower concentration of iron in human milk (0.2–0.4 mg/L) compared with infant formulas (4.0–12 mg/L) and thereby decreases competition between iron and other divalent cations, such as copper and zinc (Lonnerdal and Hernell, 1994).

In the case of LC-PUFAs, care must be taken to ensure no toxicity from these compounds. Manufacturers must study the effects of fats, minerals, enzymes, or other factors on LC–PUFA bioavailability and processing. For example, newborn fat absorption can be highly variable because of the immaturity of several lipases, including pancreatic lipase (for review, see Hamosh, 1988). Human milk contains lipases that compensate for the lack of pancreatic lipases. Thus human-milk fat is more bioavailable than the vegetable oils found in infant formulas.

Finally, manufacturers must examine the effects of infant formulas in the context of mixed feedings (Ryan et al., 2002). Throughout the course of the day, an infant in the United States may consume both human milk and infant formulas in any number of combinations. For example, some infants of working mothers are breastfed during the morning and evening and fed formula during the day by a caregiver. Here the nutrients and their respective matrixes are kept quite separate and less interaction may be expected than in the situation where an infant is supplemented with formula directly after each nursing. In the latter case there is a theoretical concern that certain nutrients found in high concentration in infant formulas (e.g., iron) may interfere with the intended matrix delivery system found in human milk (e.g., lactoferrin). The nutritional consequence of mixed-feeding paradigms has not been adequately investigated, but should be targeted in future studies of the performance of infant formulas.

Matching Breastfeeding Performance

The alternative to matching human-milk composition is to match breastfeeding performance (Benson and Masor, 1994). Initially the goal of infant formulas was to match the growth rate of the breastfed infant. However over time it was recognized that breastfeeding may confer several other potential advantages to the infant (for review, see AAP, 1997), including:

  • prevention of infectious diseases (Beaudry et al., 1995; Dewey et al., 1995),
  • neurodevelopment (Mortensen et al., 2002), and
  • protection from chronic diseases in childhood (Saarinen and Kajosaari, 1995; Shu et al., 1995).

These perceived and potential advantages of breastfeeding are the impetus behind many of the proposed addition of ingredients to infant formulas. Not all of these advantages are necessarily attributable to the nutritional content of human milk. Advantages resulting from a fundamentally different interaction between the nursing mother and her infant or to a selection bias of mothers who choose to breastfeed cannot be matched by simply adding nutrients to cow milk. It has been difficult to sort out which of the performance factors of breastfeeding are due to nutritional components and which are accounted for by social and psychological factors. Obviously, randomized trials assigning infants to breastfeed or formula feed are not ethically feasible.

Breastfeeding also confers certain risks to the developing infant, including potential nutrient deficiencies (Kreiter et al., 2000; Pisacane et al., 1995) and exposure to toxins secreted by the mother into her milk. Advantages and risks are discussed in detail below.


Breastfed infants have different growth characteristics compared with formula-fed infants. They grow at slightly different rates and have a different body composition (Butte et al., 1990; Heinig et al., 1993) and may have a lower risk for later obesity (Gillman et al., 2001; Singhal et al., 2002). (These characteristics are discussed in greater detail in Chapter 6.) Given the great interest in the effect of early nutrition on metabolic setpoints that may affect the child's risk for adult diseases (e.g., the early origins of chronic disease hypothesis) (Barker et al., 2002) and the increasing incidence of early insulin resistance, obesity, and type II diabetes in teenagers, future research should concentrate on whether breastfeeding is protective.

As discussed earlier, breastfed infants absorb fat better than formula-fed infants due to the presence of lipases in human milk that are not present in cow milk (Hamosh, 1988). The healthy breastfed infant consumes less milk (approximately 85 kcal/kg body weight/day) during the first months of life than the same infant given ad libitum infant formula (100 kcal/kg/day; Heinig et al., 1993). The breastfed infant continues to consume approximately 10 fewer kcal/kg/body weight calories than the formula-fed infant. The breastfed infant has a lower total energy expenditure (Butte et al., 1990) and a slower growth rate (Butte et al., 1990; Heinig et al., 1993). In addition, there is less gastro-esophageal reflux in breastfed infants, most likely due to a more rapid gastric emptying time, resulting in less loss of intake. Some of the trophic and metabolic factors that promote the characteristic nutrient handling and growth of the breastfed infant are listed in Table 3-1.

TABLE 3-1. Unique Factors in Human Milk That Positively Affect Nutritional Status and Somatic Growth.


Unique Factors in Human Milk That Positively Affect Nutritional Status and Somatic Growth.

Breastfed infants, compared with formula-fed infants, have a lower incidence of infectious diseases, such as diarrhea (Popkin et al., 1990), otitis media (Duncan et al., 1993), and lower respiratory tract illness (Wright et al., 1989). The effect is particularly profound in the developing world, but studies show clear advantages in the developed world as well (Wright et al., 1989). The effect extends beyond breastfeeding itself to when human milk is administered without the infant nursing from the mother. For example, preterm infants fed human milk by nasogastric tube in the newborn intensive care unit have a lower rate of necrotizing enterocolitis (Lucas and Cole, 1990). Moreover, the presence of the close contact between the mother and child stimulates the mother to make antibodies against bacteria colonized in the infant and to secrete these antibodies in her milk.

Human milk has multiple components that likely mediate this anti-infectious, immunologically enhancing effect. These include secretory immunoglobulin A, lactoferrin, lysozymes, intact cellular components, and oligosaccharides. A comprehensive list of compounds found in human milk by class of ingredient is shown in Table 3-2.

TABLE 3-2. Unique Factors in Human Milk with Anti-Infective or Immunological Properties.


Unique Factors in Human Milk with Anti-Infective or Immunological Properties.

The neurodevelopmental advantages of breastfeeding or supplying infants with human milk have received significant amounts of attention (Lucas et al., 1998; Morrow-Tlucak et al., 1988; Mortensen et al., 2002; Wang and Wu, 1996). Indeed, the primary impetus for adding LC–PUFAs to infant formulas is their postulated effect on brain development. The general research on breastfeeding, human milk, and neurodevelopment is fraught with confounding variables that have prevented pinpointing specific nutrients that are responsible for the putative effect. Overall it appears that breastfed infants have modest improvements in cognitive, motor, and visual status up to the age of 8 years, but it is unclear whether any early effects disappear over time (for review, see Grantham-McGregor et al., 1999). The degree of neurodevelopmental advantage is directly related to duration of breastfeeding (Mortensen et al., 2002). However critics of the literature point out that there may be fundamental differences not only between mothers who do or do not choose to breastfeed, but also between those who choose to breastfeed for a longer rather than shorter time period. These selection biases may be based on characteristics (e.g., maternal IQ, education, and socioeconomic status) that may confer independent positive effects on the neurodevelopment of the infant. Furthermore, patterns of parent-child interactions may be different in those who breastfeed longer; these interactions may have effects on development.

Just as it is difficult to separate out the confounding social factors among those who do and do not choose to breastfeed, it is also difficult to isolate the role of nutrition alone in the assessment of the positive effects. This is because very few individuals bottle-feed their infants human milk and, when this is done, it is frequently for medically extenuating circumstances (e.g., prematurity). Thus one cannot expect to rely on randomized trials of breastfeeding versus formula feeding or breastfeeding versus bottle feeding of human milk to sort out the nutritional effects of human milk on the developing brain. The only trial that approached this issue was conducted by Lucas and coworkers (1994), where preterm infants received either human milk or term infant formula by gavage tube during their early weeks. Infants fed bottled human milk had higher mental and psychomotor development indices 18 months after hospital discharge. However it should be reiterated that these were premature infants and that they were not randomized to their particular diets.

Nevertheless there are reasons to think that the provision of human milk, based on its composition, is good for the human brain. Human milk contains LC–PUFAs (e.g., DHA and ARA) that are important for synaptogenesis in the visual system. However studies assessing the addition of these ingredients to cow-milk formula have not resulted in consistent effects. Some demonstrated enhanced visual acuity and speed of processing in infants fed the supplemented formulas (Uauy et al., 1990; for review, see Uauy-Dagach and Mena, 1995). The positive effects on visual acuity have been found most often in premature infants, who are arguably more deficient of these fats. There may be effects on cognitive outcome, although the effects are inconsistent, particularly in term infants (Auestad et al., 2001; Wroble et al., 2002). The reason for these inconsistent effects might be that these compounds do not work alone; rather the matrix of human milk includes general growth factors and specific neural growth factors (see Table 3-3). If there is a positive effect on neurodevelopment, it is likely that these factors work in concert with each other.

TABLE 3-3. Unique Factors in Human Milk That May Positively Affect Neurodevelopment.


Unique Factors in Human Milk That May Positively Affect Neurodevelopment.

Finally, there is epidemiological evidence that breastfeeding protects infants from certain childhood diseases at older ages, including atopy/allergy (Kull et al., 2002; Saarinen and Kajosaari, 1995), obesity (Gillman et al., 2001; Singhal et al., 2002), and childhood leukemia/lymphoma (Shu et al., 1995). The biological mechanisms of the positive effects are not always clear, but may relate to avoidance of exposure to antigenic proteins found in cow milk, particularly in relation to allergy. The lack of clear biological mechanisms makes it more difficult to resolve conflicting results, such as those recently indicating an increased risk of atopy (Sears et al., 2002) and eczema (Bergmann et al., 2002) in large cohorts of breastfed infants.


Breastfeeding is not without potential nutritional risks. The best documented risks include iron deficiency (Duncan et al., 1985; Pisacane et al., 1995), vitamin D deficiency (Kreiter et al., 2000), and exposure to environmental toxins. The inability to sustain growth due to the low energy density of milk is relatively rare in the first 4 months of life in the breastfed infant. However there is great variability in the protein-energy density of human milk. Energy values may range from 15 to 24 kcal/oz. Most infants can overcome a lower-density milk by consuming a greater volume.

Iron deficiency is approximately twice as common in breastfed infants; up to 30 percent have iron deficiency anemia, and more than 60 percent of the anemic infants are also iron deficient at 12 months of age (Pisacane et al., 1995), although the etiology is unclear. The iron content of human milk is low: 0.5 mg/L compared with 10 to 12 mg/L in supplemented cow-milk formulas. The absorption rate, however, is considerably higher. Breastfed infants absorb up to 50 percent of consumed iron, compared with a 7- to 12-percent absorption rate for formula-fed infants (Fomon et al., 1993). The risk of iron deficiency increases after 4 months of age since most full-term infants are born with adequate iron stores to support hemoglobin synthesis through the first 4 months after birth.

There have been increasing reports of nutritional rickets in breastfed infants, particularly in northern climates (Kreiter et al., 2000). This is likely due to lack of sunlight exposure, which is increasingly common with the use of sunscreens and the tendency to cover infants for health or cultural reasons. Human milk, like cow milk, is very low in vitamin D, with average concentrations of 24 to 68 IU/L. Since infants consume less than 0.5 L of milk/ day in the first months of life, breastfed infants have vitamin D intake well below the Adequate Intake of 200 IU/day. With sun exposure this is not likely to be a problem. However infants born to mothers with vitamin D deficiency are at increased risk for rickets, as are those who are not exposed to the sun. The American Academy of Pediatrics and the Canadian Paediatric Society recently recommended supplementing all breastfed infants with 200 IU of vitamin D by 2 months of age (AAP, 2003; Canadian Paediatric Society, 1998).

In addition to transplacental passage of environmental allergens and dietary antigens, it is possible that susceptible infants may be sensitized to such agents by exposure to maternal milk. Although dietary antigens have been recovered in human milk, and allergen-specific IgE antibodies have been demonstrated in cord blood (Fälth-Magnusson, 1995; Lilja et al, 1988), available evidence suggests little or no role for breastmilk-associated food antigens in the development of food allergy (Businco et al., 1983; Fälth-Magnusson, 1995; Fälth-Magnusson and Kjellman, 1987).

Breastfed infants can be exposed to environmental toxins (e.g., lead and polychlorinated biphenyls), legal and illegal drugs, and infectious pathogens that the mother may harbor (e.g., Human Immunodeficiency Virus [HIV]). A discussion of all of the potential environmental toxins, drugs, and infectious agents is beyond the scope of this chapter. However it is important to note the effect of increasing rates of HIV infection worldwide and the potential for human milk to be both a vector of transmission of the virus from mother to infant and to contain protective anti-infective factors that may decrease the risk of vertical transmission. These risks and benefits must be weighed against the potential risks of formula feeding, not the least of which is preparation of formula with water contaminated with infectious agents (Humphrey and Iliff, 2001; Mbori-Ngacha et al., 2001; WHO, 1992).


This chapter affirms that breastfeeding is the standard by which all other infant-feeding methods should be judged. This position has been taken by numerous professional bodies and reflects the fact that human milk is species specific and thus uniquely suited for human infant nutrition. It must be recognized, however, that using a human-milk composition or breastfeeding performance standard presents both regulatory and research issues when assessing the addition of ingredients new to infant formulas.

From a research standpoint, clinical studies that assess the effects of new ingredients will be difficult to design because infants cannot be randomized to be formula fed or breastfed. Furthermore, there may be significant non-nutritional confounding variables between the groups, including, but not limited to, factors related to which mothers breastfeed. Finally, human-milk composition varies considerably among individuals and within individuals over time, while infant formula content remains constant.

The committee anticipates that manufacturers will wish to add both ingredients that are currently contained in human milk, but not in formulas (e.g., LC-PUFAs), and those not found in human milk (e.g., prebiotics) to enhance the performance of formulas to a level at or nearer to human milk. Thus a breastfed control group should be part of experimental designs to assess the addition of ingredients new to infant formulas in order to provide a performance standard.

From a regulatory standpoint, the effect of an ingredient new to infant formulas is usually driven by a manufacturer's desire to produce products that mimic the advantages of breastfeeding. This motivation implies that formula in its current state is inferior (e.g., relatively neurologically or immunologically less beneficial, although not necessarily unsafe) when compared with human milk. Thus the safety (and efficacy) of any addition of an ingredient new to infant formulas will need to be judged against two control groups: one fed the previous iteration of the formula without the added ingredient, and one breastfed.


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