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Comparing Infant Formulas with Human Milk

ABSTRACT

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.

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INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS

BACKGROUND

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).

HISTORY OF THE DEVELOPMENT OF INFANT FORMULAS

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

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

1915 – Formula contained cow milk, lactose, oleo oils, and vegetable oils; powdered form

1935 – Protein content of formula considered

1959 – Iron fortification introduced

1960 – Renal solute load considered; formula as a concentrated liquid

1962 – Whey:casein ratio similar to human milk

1984 – Taurine fortification introduced

Late 1990s – Nucleotide fortification introduced

Early 2000s – Long-chain polyunsaturated fatty-acid fortification introduced

Noncow-milk-based formulas

1929 – Introduction of commercially available soy formula (soy flour)

Mid 1960s – Isolated soy protein introduced

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COMPARING INFANT FORMULAS WITH HUMAN MILK

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).

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.

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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.

CHALLENGES OF MATCHING HUMAN-MILK COMPOSITION AND

BREASTFEEDING PERFORMANCE

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 LCPUFAs,

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 polyunsatu

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COMPARING INFANT FORMULAS WITH HUMAN MILK

rated 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

–

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).

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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.

PERFORMANCE ADVANTAGES OF BREASTFEEDING

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.

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.

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COMPARING INFANT FORMULAS WITH HUMAN MILK

TABLE 3-1

Unique Factors in Human Milk That Positively Affect Nutritional Status

and Somatic Growth

Ingredient Class of Ingredient Function Reference

Amylase Enzyme Polysaccharide digestion Howell et al., 1986

Epidermal growth Growth factor/hormone Gastrointestinal growth/ Donovan and Odle,

factor differentiation 1994; Dvorak et al.,

2003; Howell et al.,

1986

Erythropoietin Growth factor/hormone Red cell production; possible Kling, 2002

growth factor for gut and

central nervous system

Insulin Growth factor/hormone Anabolic hormone promotes Donovan and Odle,

carbohydrate, protein, and 1994

fat accretion

Insulin-like growth Growth factor/hormone Primary growth hormone of Donovan and Odle,

factor-I late fetal/neonatal period 1994

Insulin-like growth Growth factor/hormone Unknown function; thought Donovan and Odle,

factor-II to be weak growth hormone 1994

Lactoferrin Carrier protein Increases efficiency of iron Howell et al., 1986

delivery

Lipase Enzyme Triglyceride hydrolysis Howell et al., 1986

Nerve growth factor Growth factor/hormone Neuronal growth/ Donovan and Odle,

differentiation 1994

Proteases Enzyme Unknown if active in protein Howell et al., 1986

hydrolysis

Relaxin Growth factor/hormone Regulates morphological Donovan and Odle,

development of the nipple 1994

Transforming growth Growth factor/hormone Gastrointestinal growth Donovan and Odle,

factor-alpha 1994; Dvorak et al.,

2003

TABLE 3-2

Unique Factors in Human Milk with Anti-Infective or Immunological

Properties

Class of

Ingredient Ingredient Function Reference

Antiproteases (e.g., Enzyme Inhibits breakdown of anti- Howell et al., 1986;

secretary immuno- infective immunoglobulins IOM, 1991

globulin A and and enzymes

trypsin inhibitor)

Arylsulfatase Enzyme Degrades leukotrienes Hanson et al., 1988

Catalase Enzyme Degrades hydrogen peroxide; Lindmark-Mansson

protects against bacterial and Akesson, 2000

breeches of intestinal barrier

Fibronectin Opsonin May present debris to macrophages IOM, 1991;

Mestecky et al.,

1990

Free fatty acids Lipids Antiviral (coronavirus); antiparasitic Mestecky et al., 1990

(

Giardia, Entamoeba

)

Granulocyte-colony Cytokine Causes endothelial cell migration Wallace et al., 1997

stimulating factor and proliferation

Hemagglutinin inhibitor Opsonin Prevents bacterial adherence Neeser et al., 1988

Continued

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Histaminase Enzyme Degrades histamine Hanson et al.,1988

Immunoglobulin G Immunoglobin Immune protection Howell et al., 1986;

IOM, 1991

Interleukin-1-beta Cytokine Activates T-cells Mestecky et al., 1990

Interleukin-6 Cytokine Enhances immunoglobulin A Mestecky et al., 1990

and C-reactive protein production

Interleukin-8 Cytokine Chemotaxis Maheshwari et al.,

2002

Interleukin-10 Cytokine Decreases inflammatory cytokine Goldman et al., 1996

synthesis

Lactadherin Protein Prevents rotavirus binding Peterson et al., 2001

Lactoferrin Carrier Anti-infective; may prevent iron Howell et al., 1986;

from being bioavailable to IOM, 1991

microbes

Leukocytes Live cell Cytokine production by T-cells; IOM, 1991;

direct in vivo roles of B-cells, Mestecky et al.,

macrophages, and neutrophils 1990

Lipases Enzyme Releases bacteriostatic and Howell et al., 1986;

bacteriocidal free fatty acids IOM, 1991

Lysozyme Enzyme Bactericidal Howell et al., 1986;

IOM, 1991

Macrophage colony Cytokine Macrophage proliferation Goldman et al., 1986

stimulating factor

Mucin Protein Inhibits

E. coli

binding Peterson et al., 2001

to gut epithelium

Oligosaccharides, Carbohydrates, Receptor analogs block Coppa et al., 1999;

polysaccharides, glycoconjugates binding of enteric bacteria; IOM, 1991;

gangliosides growth promoters for Rivero-Urgell and

Lactobacillus

Santamaria-

Orleans, 2001

Peroxidases Enzyme Bactericidal Howell et al., 1986;

IOM, 1991

Platelet activating Enzyme Catabolizes platelet Furukawa et al.,

acetyl hydrolase activator factor 1993

factor

Prostaglandin E2, Prostaglandin Intestinal cytoprotection Howell et al., 1986

F2-alpha

Ribonuclease Enzyme Prevents viral replication Nevinsky and

Buneva, 2002

Secretory Immunoglobulin Immune protection (broad Howell et al., 1986;

immunoglobulin A spectrum antiviral, antibacterial, IOM, 1991

antiparasitic)

Soluble intracellular Cytokine Alters adhesion of viral or Xyni et al., 2000

adhesion molecule-1 other molecules to intestinal

epithelium

Transforming growth Cytokine Produces immunoglobulin A Bottcher et al., 2000

factor-beta and activates B-cells

Tumor necrosis Cytokine Mobilizes amino acids Mestecky et al., 1990

factor-alpha

Uric acid Small molecular- Antioxidant Van Zoeren-Grobben

weight et al., 1994

nitrogenous

compound

TABLE 3-2

continued

Class of

Ingredient Ingredient Function Reference

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COMPARING INFANT FORMULAS WITH HUMAN MILK

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.

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

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risk of atopy (Sears et al., 2002) and eczema (Bergmann et al., 2002) in large cohorts of

breastfed infants.

RISKS OF BREASTFEEDING

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 lowerdensity

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).

TABLE 3-3

Unique Factors in Human Milk That May Positively Affect

Neurodevelopment

Ingredient Class of Ingredient Function Reference

Choline Amino acid Neurotransmitter Zeisel et al., 1986

synthesis

Insulin-like growth factor-1 Growth factor/hormone Neuronal growth/ Cheng et al., 2003;

differentiation Donovan and Odle,

1994

Long-chain polyunsaturated Essential/semiessential fat Visual acuity Uauy-Dagach and

fatty acids Mena, 1995

Nerve growth factor Growth factor/hormone Neuronal growth/ Donovan and Odle, 1994

differentiation

Oligosaccharides (fucose, Carbohydrates Neuronal cell-cell Hynes et al., 1989

mannose,

-acetylglucosa- communication

mine, sialic acid)

Infant Formula: Evaluating the Safety of New Ingredients

http://www.nap.edu/catalog/10935.html

COMPARING INFANT FORMULAS WITH HUMAN MILK

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 (F

lth-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; F

älth-Magnusson, 1995; Fä

lth-

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).

SUMMARY

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.