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Breastfeeding: Unraveling the Mysteries of Mother's Milk

Margit Hamosh, PhD, Georgetown University Medical Center

Medscape General Medicine 1(1), 1999. © 1999 Medscape

Posted 09/15/1996

Abstract and Introduction

Abstract

Most of the major progress in understanding the unique and complex features of human breast milk has emerged in just the past 2 decades. Since the late 1970s, key research has examined such aspects as the composition of breast milk, effects of maternal and environmental factors on human milk, and the effect of human milk on the infant, including the protection against disease that breast milk can confer on the newborn. The composition of human breast milk includes growth factors, hormones, enzymes, and other substances that are immune-protective and foster proper growth and nutrition in the newborn. Research suggests that lactation is robust and that a mother's breast milk is adequate in essential nutrients, even when her own nutrition is inadequate. Mature breast milk usually has constant levels of about 7g/dL carbohydrate and about 0.9g/dL proteins. But the composition of fats essential for neonatal growth, brain development, and retinal function varies according to a woman's intake, the length of gestation, and the period of lactation. Vitamins and minerals also vary according to maternal intake. But even when these nutrients are lower in breast milk than in formulas, their higher bioactivity and bioavailability more nearly meet the complete needs of neonates than do even the best infant formulas. Also, in many instances human milk components compensate for immature function, such as a neonate's inability to produce certain digestive enzymes, immunoglobulin A (IgA), taurine, nucleotides, and long-chain polyunsaturated fatty acids.

Introduction

Even when a mother's own supply of nutrients and energy is limited, she still is able to produce breast milk of sufficient quantity and quality to support the growth and health of her infant. This finding that "lactation is robust" is one of several discoveries to emerge in recent years.[1] The quest to better understand the complex features of human breast milk has been building in the past 2 decades, as evidenced by the growing number of international meetings, expert work groups, and publications focusing on human breast milk. Since the late 1970s, key research has addressed such topics as analyzing human milk,[2-4] identifying how maternal and environmental factors affect breast milk,[5] and determining the effect of human milk on the infant,[6,7] including the protection against disease that breast milk can confer on the newborn.[8]

Human milk, like the milk of many other mammals, is specifically adapted to the needs of the newborn. Before birth, the mother transfers nutrients and bioactive components through the placenta[9]; after birth, these substances are transferred through colostrum and milk. In contrast to infant formula, human milk offers the infant nutrients with high bioavailability as well as a large number of bioactive components that confer immune and nonimmune protection against pathogens in the infant's environment. Also, in many instances human milk components compensate for immature function, such as a neonate's inability to produce certain digestive enzymes, immunoglobulin A (IgA), taurine, nucleotides, and long-chain polyunsaturated fatty acids (LC-PUFA), among other substances. Because many of these components remain intact during pasteurization, it is more advisable to feed pasteurized human donor milk to infants whose mothers are unable to nurse than it is to substitute formula.[1] Its bioactive components make human milk superior to even the best infant formulas.

Milk Volume and Composition

Volume. Milk volume is relatively constant irrespective of maternal nutritional status (Fig. 1). In general, healthy infants consume an average of 750-800mL milk daily for the first 4-5 months after birth (range, 450 to 1200mL/day).[1,10,11] Similar findings were reported from developing countries where maternal nutrition is sometimes subject to greater seasonal variation and may be less adequate compared with industrial countries.[1,11] Increasing the intake of fluid does not seem to affect milk volume.[10] Therefore, lactating women should maintain adequate fluid intake but should not attempt to boost milk volume by consuming excess fluids.[1]

Figure 1. In general, healthy infants consume 450 to 1200mL/day first 4-5 months after birth. Milk volume is relatively constant irrespective of maternal nutritional status. Photo courtesy of Susanrachel Condon.

Major nutrients. Lactose, 5.5-6.0g/dL, is the most constant nutrient in human milk (Table I). Its concentration in breast milk is not affected by maternal nutrition.

Proteins amount to about 0.9g/dL in mature milk.[12]Recent studies comparing the impact of nutrition on lactation in industrialized and developing countries suggest that neither maternal diet nor body composition affects milk protein level.[1] However, limited data from earlier studies seem to indicate that short-term, high-protein diets can increase the protein and nonprotein nitrogen content of human milk,[13] while limiting maternal food intake can lead to lower milk protein levels.[13-15]

The majority of milk proteins provide the newborn with immune and nonimmune protection from infection. These proteins--immunoglobulins A, G, and M; lactoferrin; and lysozyme--have various functions in the newborn.[16] Early studies suggested that the level of these protective proteins in milk is affected by maternal diet, but more recent research suggests that immunoglobulins might be stable for a wide range of diets.[17-20]

Fat. While the amount and composition of carbohydrate and protein remain relatively constant in mature human milk, the composition of fat is highly variable and is affected within hours and to a large extent by maternal nutrition intake.[21] Gestation, lactation, parity, milk volume, caloric and carbohydrate intake, and weight changes are among the maternal factors that can alter the fat content and composition of breast milk. Specifically, phospholipid and cholesterol content are higher in colostrum preterm than term breast milk. Also, long chain polyunsaturated fatty acids (LC-PUFA) are higher in preterm and transitional milk and remain high for the first 6 months in women who deliver preterm. In term milk, on the other hand, LC-PUFA declines throughout the first 6 to 12 months of lactation. The endogenous synthesis of fatty acids (FA) declines with parity, most notably after 10 births, but FAs (C6-C16) rise with a high-carbohydrate diet. Palmitic acid (C16) content of breast milk increases in a low-calorie diet. Weight gain during pregnancy is positively associated with higher milk fat content. During infant feedings, fore milk has less fat content than hind milk. Also, the higher the volume of breast milk, the lower the milk fat concentration.[92] The lengths of both gestation and lactation affect phospholipid and cholesterol, the lipids that constitute the milk fat globule membrane.[22] In the early stage of lactation, because the milk fat globules are much smaller than in mature milk,[23,24] the total "membrane" lipid level is higher in colostrum and transitional milk than in mature milk. The period of colostrum lasts less than 10 days, but during this short time the higher lipid levels are beneficial in such processes as neonatal cell membrane production needed for growth, brain development, and bile salt synthesis. LC-PUFAs--C20:4n6 and C22:6n3, arachidonic, and docosahexaenoic acids, respectively--are milk fats essential for neonatal growth, brain development, and retinal function.[25,26] These fatty acids are stored in the fetus only in the last trimester of pregnancy; therefore, preterm infants are born with low reserves of LC-PUFA, and their best source for these essential fatty acids is human milk. LC-PUFA levels normally decrease in breast milk during lactation, but in women who have delivered infants before term, the levels remain constant in preterm milk for at least 6 months[27]. Holman and colleagues[28] have reported that levels of LC-PUFA often decline in pregnant and lactating women, suggesting that there is a preferential transfer of these essential fatty acids from mother to fetus or to the newborn through milk, even at the cost of possible depletion of maternal reserves. Depletion of maternal reserves might suggest the need for supplementation of pregnant and lactating women with LC-PUFA.

Milk fat content changes dramatically during each feeding[29,30] and fat composition is markedly affected by the maternal diet.[31] Some studies have shown that the mechanism for endogenous synthesis of fatty acids (ie, mainly medium chain fatty acids) seems to become exhausted in women of very high parity[32]; that infants who receive milk with low fat content (ie, less than 3.0 g/dl when the norm is 3.5 to 4.5 g/dl) tend to nurse more frequently and for longer time periods, thereby causing an increase in milk volume[33]; and that there is a strong positive relationship between weight gain during pregnancy and milk fat content.[34]

Vitamins and minerals. The vitamin content of human milk depends on the mother's vitamin status; when maternal intake of specific vitamins is chronically low, these vitamins in turn are found in low levels in the milk. Vitamin supplementation raises vitamin concentrations in milk. Water-soluble vitamins in milk are generally more responsive to maternal dietary intake than fat-soluble ones.[1]

The relationship between maternal intake of vitamins and their concentration in milk varies according to the specific vitamin. For example, excess vitamin C intake does not further increase the level in milk (above that associated with adequate intake), whereas vitamin B6 concentrations in milk continue to rise with higher intakes. Folate levels in milk remain normal even at the expense of maternal folate stores and do not decrease until the latter are depleted.[1] Based on infant needs and the concentrations of fat-soluble vitamins in human milk, the Institute of Medicine (IOM) advises that in the US all newborns receive 0.5-1.0mg vitamin K by injection or 1.0-2.0mg orally immediately after birth.[1,10] Infants should receive 5.0-7.5ug vitamin D per day if exposure to sunlight seems inadequate.

The concentration of trace minerals (iron, copper, zinc, selenium) varies as a function of length of lactation. Concentrations of iron[35,36] and fluoride[37] in milk seem to be independent of maternal nutrition. Concentrations of manganese,[38] iodine,[39] and selenium[40] depend on maternal nutrition. Iodine is unique among trace elements in that it is avidly accumulated by the mammary gland[1].

Because of the high bioavailability of iron in human milk, exclusively breast-fed infants do not need iron supplements during the first 6 months of life. When supplementary foods are introduced (as recommended after 4-6 months of exclusive breast-feeding), iron supplements should be added to the infant's nutrition[35, 36]. It is recommended that breast-fed infants receive supplemental fluoride if the water supply in the area has only low levels (<0.3ppm).

It is important to assess not only the concentration of milk components but also the amount delivered to the infant. Thus, while some milk components are present at a higher concentration in colostrum than in milk, one has to consider the marked differences in volume: colostrum amounts to about 100mL/day, whereas average milk volumes are 750-850mL/day.

Bioactivity of Human Milk

Breast milk provides not only essential nutrients but also a great number of other specific functions in the newborn. For example, major nutrients, protein, carbohydrate, and fat, in addition to serving as building blocks for the infant's tissue, carry out anti-infective as well as nutrient-enhancing functions, such as transporting essential elements and aiding digestion. Furthermore, even when concentrations in human milk are markedly lower than in bovine milk or formula, nutrients from human milk might have much greater bioavailability for the infant because of specific biologic factors, such as the infant's receptor-mediated uptake of iron from human milk. Thus, in spite of a relatively low concentration of some nutrients, human milk might be superior to other nutrient sources in providing these nutrients to the infant. The apparently lower concentration of some nutrients in human milk such as vitamin D, pantothenic acid, and folate, might be due to the fact that they are bound to other components or, lower concentrations may be due to shifts from the aqueous phase to the fat phase of milk upon standing after the milk has been expressed from the breast (vitamin D).

Immune and Nonimmune Protecting Agents

All proteins in human milk have bioactive functions in addition to providing amino acids for protein synthesis by the newborn. Whey proteins, for example, have been reported to provide immune and nonimmune protection.[41,42] Recently, casein has been shown to prevent the attachment of Helicobacter pylori to human gastric mucosa.[43]

Most proteins in human milk are heavily glycosylated[44] and are therefore resistant to proteolysis both after ingestion by the infant[42,45] and after short-term storage (4-24 hours) at low to moderate ambient temperatures (15deg.-25deg.C).[46,47]

Early in studies of human milk, researchers became aware that certain substances--most notably, IgA, lysozyme, and lactoferrin--that are abundant in human milk (compared with bovine milk)[41] might protect the infant from infection.[47] This observation has progressed within the last 2 decades to a fuller appreciation of several characteristics of breast milk's protective features:

  • Immunoprotective substances act at mucosal sites.
  • Because of their resistance to digestive enzymes, protective factors are well adapted to persist in the hostile environment of the gastrointestinal tract.
  • They kill certain bacterial pathogens synergistically.
  • Protection is achieved without triggering inflammatory reactions.
  • The daily production of many immunoprotective factors changes as lactation proceeds.
  • The secretion of many soluble defense agents by the mammary gland is inversely related to the capacity of the recipient infant to produce them at mucosal sites.[41, 49-51]
The presence in milk of immunomodulators that fine-tune the interrelationships among the various protective agents has recently been reported and is currently being investigated (Table II).[52] Secretory immunoglobulin A (sIgA), dimeric IgA coupled to the secretory component, is the main immunoglobulin in human milk. IgG and IgM are also present in milk, but at much lower concentrations. The changing concentration of these immunoglobulins in milk provides an example of the interaction between milk components and the functional development of the infant: while IgG and IgM rise rapidly after birth, the newborn maintains low levels of endogenous IgA during the first year of life. IgA is produced in the mammary gland in B cells, which originate at maternal sites of high environmental pathogen exposure (eg, the small intestine or respiratory tract), and therefore protects the infant against pathogens present in the immediate environment.

Table III summarizes the enteric and respiratory pathogens against which the infant is protected by specific IgA antibodies in human milk. IgA is resistant to proteolysis, acts at mucosal surfaces, and protects by noninflammatory mechanisms; all of these properties enable efficient action in the infant.

Human milk lacks inflammatory mediators, and contains anti-inflammatory agents such as antiproteases, antioxidants, and enzymes that degrade inflammatory mediators and modulators of leukocyte activation (Table IV).[49] Furthermore, IgE (the principal immunoglobulin responsible for immediate hypersensitivity reactions), basophils, mast cells, eosinophils (the principal effector cells in these reactions), and the mediators from these cells are absent in human milk. Immune and nonimmune protecting agents are present in milk throughout lactation and some, such as lysozyme, are present at higher concentrations during prolonged lactation than during the early stages. Therefore, although it is strongly advocated that breast-fed infants receive food supplements after 4 to 6 months of exclusive breast-feeding, it is advisable to breast-feed for longer periods in geographic areas where the environment may be contaminated with pathogenic microorganisms, in order to provide the infant and toddler the benefits of milk-borne protective agents.

Studies also indicate that a glycoconjugate present in human milk, but absent in either human serum or bovine milk, inhibits the binding of HIV envelope glycoprotein (gp120) to the CD4 receptor of T lymphocytes.[53,54]

In addition to soluble antigens and anti-infective agents, human milk contains leukocytes; the majority (90%) are neutrophils and macrophages. Lymphocytes account for approximately 10%. The number and type of leukocytes change with duration of lactation. Most of the lymphocytes in milk are T cells. The proportions of CD4 (helper) to CD8 (suppressor/cytotoxic) cells in human milk are similar to those in blood. Cytokines in human milk (eg, TNF-alpha and IL-1-beta) have been shown to enhance the anti-infective function of milk leukocytes. Milk macrophages might participate in the process of immunogenesis in the infant.

The immune and nonimmune protection provided by milk results in a lower incidence of necrotizing enterocolitis[55] and other gastrointestinal and respiratory infections in breast-fed infants than in formula-fed infants[56]. The incidence of otitis media is also lower than in formula-fed infants. In addition to protection against some infectious diseases, breast-fed infants might also be protected at later ages from diseases that are sequelae of infectious insults (eg, insulin-dependent diabetes mellitus, lymphoma, and Crohn's disease). Immune factors provided by human milk that compensate for their delayed production by the infant are summarized in Table V.

Oligosaccharides (which amount to 1.0-1.5g/100mL of human milk),[53] glycoconjugates, mucins, and glycolipids act as receptor analogs and thereby inhibit the binding of enteric and respiratory microorganisms and their toxins.[57] In addition, the hydrolysis of milk triglycerides (the major component of milk fat) during digestion in the stomach and intestine[59] produces free fatty acids and monoglycerides that have been shown to have antiviral, antiprotozoan, and possibly also antibacterial activity.[60]

Growth Factors and Hormones

The presence of growth factors and hormones in milk and their function has been known for some time (Table VI, VII).[61-64] Interestingly, the concentration of many growth factors and hormones is higher in a woman's milk than in her plasma. The milk hormones, however, often differ in structure from their maternal serum counterparts, suggesting modification (often post-translational processing such as glycosylation) within the mammary gland. These glycosylated forms often are difficult to detect by standard RIA techniques and have to be quantitated by specific bioassays.[62] The stronger glycosylation protects these bioactive components during passage through the gastrointestinal tract and probably enables the newborn to absorb growth factors and hormones from mother's milk.

It appears that variants of prolactin are present in the circulation of the newborn and that the prolactin acquired from breast milk, and not endogenous prolactin secreted by the newborn's pituitary gland, is essential for the normal development of the neuroendocrine regulation of prolactin in the newborn.[62,65]

Many hormones act in the newborn. While the exact mechanisms of uptake from milk and their mode and site of action in the newborn are known for some, further study is needed to identify these mechanisms for most hormones. Agents in milk seem to stabilize hormones in the gastrointestinal tract of the newborn.

In addition to prolactin, other hormones such as progesterone are present in different form in breast milk than in maternal serum. Transfer of these hormones from milk to infant was documented in some studies directly; in other studies, this transfer is inferred from the documentation of higher serum level of the hormone--for example, thyrotropin releasing hormone (TRH) and somatostatin--in breast-fed than in formula-fed newborns[61]. The milk hormones may also be modified as they pass through the gastrointestinal tract and prior to release into the newborn's blood.

Enzymes

Human milk contains a great number of enzymes, many of which have specific transport functions (Table VIII). For instance, xanthine oxidase acts as a carrier of iron[65] and glutathione peroxidase carries selenium.[66] Although proteases are present in human milk, it is not known how much of that activity is expressed because of the antiprotease activity of human milk itself.[66] One can postulate that antiproteases might protect the mammary gland from local proteolysis (caused by leukocytic or lysosomal proteases) and might prevent the proteolytic breakdown of milk proteins, many of which have to reach the infant intact (eg, immunoglobulins, digestive enzymes). The antitryptic and antichymotryptic activity of human milk might prevent the absorption of endogenous and bacterial proteases in infants and thereby contribute to the passive protection of extraintestinal organs such as the liver.[67] The high activity of antiproteases in colostrum coincides with the period of greatest transfer of nonimmunoglobulin protein from the intestine to the systemic circulation of the newborn.

The digestive enzymes in milk (amylase and digestive lipase) act in the newborn to compensate for immature pancreatic function. These enzymes are remarkably stable for years in milk stored at low temperature (-20deg.C or -70deg.C). Moreover, activity is unchanged after storage for 24 hours at 38deg.C. The stability of enzymes and of other proteins in milk might be due to the antiprotease activity of milk. Furthermore, many enzymes are stable in the gastrointestinal tract of the newborn.

Amylase,[68] an enzyme identified in milk more than a century ago,[69] may be more important to the infant after initiation of starch supplements[70] or when formula that contains oligosaccharides hydrolyzed by amylase is fed to partially breast-fed infants. Amylase activity in the duodenum of the newborn is only 0.2% to 0.5% of the adult level. At the time of supplementation (after 4 to 6 months of exclusive breast-feeding), the infant is still deficient in endogenously produced amylase.[71] The latter secreted from salivary glands and pancreas does not reach adequate levels until 2 years after birth. Other infants and toddlers who might benefit from milk amylase are those with pancreatic insufficiency caused by diseases such as cystic fibrosis[72] or malnutrition.[73-75] Because of the potential of bile salt-dependent lipase in milk[76] to compensate for the low pancreatic lipase in the newborn,[77,78] this enzyme has received great attention in the past decade.[44,66] The characteristics of the digestive enzymes of human milk are summarized in Table IX.

Other Essential Components in Human Milk

Several milk components are essential because they have to be provided to the newborn, while older children and adults have the ability to synthesize these components. Among these are carnitine,[79] taurine,[80] and LC-PUFAs[26] that are produced by elongation and desaturation of the precursor fatty acids, linoleic (C 18:2, n-6), and linolenic (C18:3, n-3) acids, and nucleotides[81] that have to be provided to the intestine and lymphatic tissues because they cannot be synthesized either from the diet or de novo in other organs.[82] The need for these essential components might be even greater in premature infants who are born before fetal intrauterine reserves have been laid down.

The breakdown of milk casein produces beta-casomorphins; these short peptides have been shown to affect a variety of physiologic systems.[83] Because they are opioid agonists, these peptides also have behavioral effects, such as lowering response to pain and elevating mood, that can affect the nursing mother or the newborn. Most of the effects of the beta-casomorphins have been studied in such animals as rats, pigs, and chickens[83].

Human Milk After Preterm Delivery

The milk produced by women who deliver prematurely differs from that produced after a full-term pregnancy. Specifically, during the first month after parturition, preterm milk maintains a composition similar to that of colostrum. Colostrum, secreted during the first few days after parturition, contains higher concentrations of protein (including higher levels of protective proteins such as secretory IgA, lactoferrin, and lysozyme), sodium, and chloride, and contains lower amounts of potassium, carbohydrate, fat, and certain vitamins. While the transition from colostrum to mature milk is rapid after full-term pregnancy, it proceeds much more slowly after premature delivery.[84]

Some of the nutritional needs of preterm infants, therefore, cannot be met by feeding the preemie breast milk only. While the mother's own preterm milk is preferable to donor-banked full-term milk, either diet has to be supplemented with protein, calcium, and phosphorus in the preterm infant.[85] However, given the many benefits to the preterm infant that accrue from the mother's own milk, efforts should be made to encourage mothers of preterm infants to breast-feed, even if during the early stages this might necessitate milk pumping while the infant is hospitalized or is too immature to nurse.

Long-Term Effects of Breast-feeding

Human milk not only is beneficial during infancy,[1,2,7,8] but it also may protect the child from chronic diseases that develop at later ages, such as Crohn's,[86] diabetes mellitus,[87] and lymphomas.[88] Also, cognitive development, assessed at 7.5-8.0 years of age, seems to be affected by early diet in the preterm infant. A significantly higher score on the Wechsler Intelligence Scales for Children-Revised (WISC-R) was found in children fed expressed human milk than in those fed formula in early infancy.[89,90] Similar findings have been reported for full-term infants.[91]

Conclusion: Continuing the Progress in Understanding and Promoting Breast-feeding

Given the short-term and long-term benefits of breast-feeding, many working women continue to breast-feed after returning to work. Collection and proper storage of milk in the workplace might not always be easy, because it may be difficult to find a quiet, isolated place where the mother can pump milk, or a refrigerator for milk storage. However, one study showed that milk can be safely stored for up to 24 hours at 60deg.F,[47] a temperature that can be maintained in a styrofoam box with a frozen ice pack. Efforts should be made to make the workplace an easier environment in which women who choose to breast-feed can do so.

We have just begun to assess the many components in human milk and their interaction with the infant. Much work lies ahead to understand in depth the immediate and long-term effects of feeding mother's milk to newborns. As researchers continue to discover the unique features of breast milk, clinicians need to encourage the practice for the sake of the benefits breast-feeding can bring to both mothers and infants.

Tables

Table I. Concentrations of Nutrients in Mature Human Milk


Major nutrientsg/liter
Carbohydrate72.0±2.5
Protein10.5±2.0
Fat39.0±4.0
Macronutrients
Mineralsmg/liter
Calcium280±26
Chloride420±60
Magnesium35±2
Phosphorus140±22
Potassium525±35
Trace Elementsug/liter
Chromium50±5
Copper250±30
Fluoride16±5
Iodine110±40
Iron300±100
Manganese6±2
MolybdenumNR
Selenium20±5
Zinc1200±200
Vitamins
Fat-solublemg/liter
Vitamin A, RE*670±200 (2230 IU)
Vitamin D0.55±0.10
Vitamin E2300±1000
Vitamin K2.1±0.1
Water-solublemg/liter
Vitamin B693,000±8,000
Vitamin B120.97
Biotin4±1
Vitamin C40,000±10,000
Folate85±37
Niacin1500±200
Pantothenic acid1800±200
Riboflavin350±25
Thiamin210±35

Reprinted from Hamosh et al: Nutrition During Lactation, (1991, p 116), Copyright (c) 1991, National Academy Press.Data (means ± SD); IU = international units; NR = not reported; RE = retinol equivalents.


Table II. Cytokines in Human Milk: Mean Concentrations and Potential Functions*


CytokinesPossible FunctionsConcentrations
IL-1bActivates T cells~ 1130pg/mL
IL-6 Enhances IgA production~ 151pg/mL
IL-8Chemotaxin for neutrophils/T cells~ 3500pg/mL
IL-10Decreased inflammatory cytokine synthesis~ 3500pg/mL
TNF-aIncreased secretory component production ~ 620pg/mL
TGF-bEnhances Ig isotype switching to IgA+ B cells~ 130pg/mL
M-CSFInduce proliferation and differentiation of macrophages~ 2000-9000 U/mL

*Milk collected during the first several days of lactation. Data are mean values.
From Goldman AS, et al.[42]


Table III. Enteric and Respiratory Pathogens Commonly Targeted By Secretory IgA Antibodies Found in Human Milk


Enteric PathogensRespiratory Pathogens
* Bacteria, Toxins, Virulence Factors
Clostridium difficile
Escherichia coli
Salmonella spp
Shigella spp
Vibrio cholerae

* Parasites
Giardia lamblia

* Viruses
Polioviruses
Rotaviruses
* Bacteria
Haemophilus influenzae
Streptococcus pneumoniae
Klebsiella pneumoniae

* Viruses
Influenza viruses
Respiratory syncytial virus

* Fungi
Candida albicans

* Food Proteins
Cow's milk
Soy

From Goldman AS, Goldblum RM. Immunologic systems in human milk: Characteristics and effects, in Lebenthal E (ed): Textbook of Gastroenterology and Nutrition in Infancy, ed 2. New York, Raven Press, 1989, pp 135-142.


Table IV. Anti-Inflammatory Components in Human Milk


Component EnzymesFunction
CatalaseDegrades hydrogen peroxide
HistaminaseDegrades histamine
ArysulfataseDegrades leucotrienes
Antioxidants
a-Tocopherol
Cysteine
Ascorbic acid		Scavengers of oxygen radicals
Antiproteases
a -1-antitrypsin
a -1-antichymotrypsin		Neutralize enzymes that act in inflammation
Prostaglandins
PG-E2
PG-F2		Cytoprotective

Reprinted from Acta Paediatr Scand (1986; 689), Copyright (c) 1986, Scandinavian University Press.


Table V. Immune Factors in Human Milk that Compensate for Delayed Production in Infants


Immune Factors in Human MilkWhen Immune Factors Mature in the Infant
Secretory IgA (sIgA)~ 4-12 months
Full antibody repertoire~ 24 months
Lysozyme~ 1-2 years
Lactoferrin?
Interleukin-6?
PAF-acetylhydrolase?
Memory T cells2 years

Reprinted from Pediatr Infect Dis J (1993; 12:664-672), Copyright (c) 1993, Williams and Wilkins.


Table VI. Growth Factors in Human Colostrum and Milk


Growth FactorColostrumMilk
EGF*6-73 nM3-19 nM
NGFNot quantified 
Insulin*21.5±5mg/L2.6±0.3mg/L
IGF-I10.9±5.3mg/L7.1-19.1mg/L
IGF-IINR2.7±0.7mg/L
Relaxin327±110mg/L509±5.3ng/L
TGF-a2.2-7.2mg/L0-8.4mg/L

* EGF concentration higher in preterm colostrum and milk, insulin concentration lower in preterm colostrum and milk than in term milk. From Donovan et al. [64]


Table VII. Function of Milk-Growth Factors and Hormones in the Mammary Gland and Newborn


Growth Factor/HormoneMaternal Mammary GlandNewborn
PRLMaintenance of lactationNeuroendocrine and immune system
CorticosteroneSynthetic capacity (enzymes, specific proteins, etc.)Response to stress in the adult
InsulinGrowth via IGF-II or IGF-INeonatal glycemia
IGFsGrowth and (?) differentiation of glandGI growth, affect IGF receptors in intestine (?) systemic growth effects
RelaxinGrowth and differentiation 
EGF, TGF-aGrowthGI growth, gut closure, eye opening
TGF-bInhibits growthInhibits enterocyte growth in ovarian GnRH receptors
GnRH (?) GH secretion
GRH (?) GH secretion
TRH (?) TSH secretion
PTHrP(?) Ca/P/Mg in milk 
Salmon calcitonin-like peptidePRL inhibiting factor 
Erythropoietin Stimulates erythropoiesis
ProstaglandinsCytoprotection for intestine 

EGF: epidermal growth factor; IGF: insulin like growth factor; PRL: prolactin.
From Grosvenor et al.[62]


Table VIII. Functions of Enzymes in Human Milk


FunctionEnzyme(s)Process(s)
Biosynthesis of milk components in the mammary glandPhosphoglucomutaseSynthesis of lactose
Lactose synthetaseSynthesis of lactose
Fatty acid synthetaseSynthesis of medium-chain fatty acids
Lipoprotein lipaseUptake of circulating triglyceride fatty acids
Digestive function in the infantAmylaseHydrolysis of polysaccharides
Lipase (bile salt-dependent)Hydrolysis of triglycerides
Proteases*Proteolysis (not verified)
Transport in the infantXanthine oxidaseCarrier of iron, molybdenum
Glutathione peroxidaseCarrier of selenium
Alkaline phosphataseCarrier of zinc, magnesium
Preservation of milk componentsAntiproteasesProtection of bioactive proteins (ie, enzymes and immunoglobulins)
Sulfhydryl oxidaseMaintenance of structure and function of proteins containingS-S bonds
Anti-infective agentsLysozymeBactericidal
PeroxidaseBactericidal
Lipases (lipoprotein lipase, bile salt-dependent lipase)Release of free fatty acids that have antibacterial, antiviral,and antiprotozoan actions
Protection against enterocolitisPAF-AHHydrolysis of platelet necrotizing activity factor

*It is not known whether the proteolytic enzymes of milk are active because of possible interaction with milk antiproteases. PAF-AH = Platelet activity factor acetyl hydrolase.
From Hamosh.[66]


Table IX. Characteristics of Milk Enzymes Active in Infant Digestion Enzyme


Characteristic Maternal factorsAmylaseBile salt-dependent lipase
High parity (>10)Low activity?
Malnutrition?Decrease in activity
Diurnal and within feed activityConstantConstant
Pattern of secretion
Prepartum?Present
ColostrumColostrum greater than milkColostrum lower than milk
Milk after preterm (PT) and term (T) deliveryEqual activity PT and TEqual activity PT and T
Weaning?Activity constant independent of milk volume
Distribution in milkAqueous phaseAqueous phase
Effect of milk storage Temperature
Cold: -20deg.C to -70deg.CStableStable
Warm: +15deg.C to +38deg.CStable (at least 24 hrs) 
Stable (at least 24 hrs)  
Effect of pH
Low pH (pH>3.0) (passage through stomach)StableStable
pH optimum6.5-7.57.4-8.5
Enzyme characterIdentical to salivary amylase isozymeIdentical to pancreatic carboxyl ester lipase
Evidence of activity in infant's intestineYesYes
Presence in milk of other species?Yes, in primates and carnivores

From Hamosh.[66]


References

  1. Hamosh M, Dewey, Garza C, et al: Nutrition During Lactation. IOM, Washington, DC, National Academy Press, 1991, pp. 11, 16, 131, 160-161, 179.
  2. Jensen RG, Neville MC (eds): Human Lactation: Milk Components and Methodologies. New York, Plenum Press, 1985, pp 307.
  3. FASEB (Federation of American Societies for Experimental Biology): Proceedings of Mini Symposium at 1983 Annual Meeting of the Federation of American Societies for Experimental Biology. J Pediatr Gastroenterol Nutr 3, 1984.
  4. Jensen RG (ed): Handbook of Milk Composition. San Diego, Academic Press, 1995.
  5. Hamosh M, Goldman AS (eds): Human Lactation 2: Maternal and Environmental Factors. New York, Plenum Press, 1986, pp 657.
  6. Picciano MF, Lonnerdal B: Mechanisms Regulating Lactation and Infant Nutrient Utilization. New York, Wiley-Liss Inc, 1992, pp 463.
  7. Goldman AS, Atkinson SA, Hanson LA: Human Lactation 3: The Effects of Human Milk on the Recipient Infant. New York, Plenum Press, 1987, pp 400.
  8. Mestecky J, Blair C, Ogra PL: Immunology of Milk and the Neonate. New York, Plenum Press, 1991, pp 483.
  9. King JC, Butte NF, Chez RA, et al: Nutrition During Pregnancy. IOM, Washington, DC, National Academy Press, 1990, pp 468.
  10. Neville MC, Keller R, Seacat J, et al: Studies in human lactation: Milk volumes in lactating women during the onset of lactation and full lactation. Am J Clin Nutr 48(6):1375-1386, 1988.
  11. Prentice A, Paul A, Prentice A, et al: Crosscultural differences in lactational performance, in Hamosh M, Goldman AS (eds): Human Lactation 2: Maternal and Environmental Factors. New York, Plenum Press, 1986, pp 13-44.
  12. Lonnerdal B, Forsum E, Hambraeus L: A longitudinal study of the protein, nitrogen, and lactose contents of human milk from Swedish well-nourished mothers. Am J Clin Nutr 29:1127-1133, 1976.
  13. Deb AK, Cama HR: Studies on human lactation: Dietary nitrogen utilization during lactation, and distribution of nitrogen in mother's milk. Br J Nutr 16:65-73, 1962.
  14. Lindblad BS, Rahimtoola RJ: A pilot study of the quality of human milk in a lower socioeconomic group in Karachi, Pakistan. Acta Paediatr Scand 63:125-128, 1974.
  15. Wurtman JJ, Fernstrom JD: Free amino acid, protein, and fat contents of breast milk from Guatemalan mothers consuming a corn-based diet. Early Hum Dev 3:67-77, 1979.
  16. Hamosh M: Human milk composition and function in the infant. Seminar Pediatr Gastroenterol Nutr 3:4-8, 1992.
  17. Cruz JR, Carlsson B, Garcia B: Studies in human milk. III. Secretory IgA quantity and antibody levels against Escherichia coli in colostrum and milk from under-privileged and privileged mothers. Pediatr Res 16:272-276, 1982.
  18. Reddy V, Srikantia SG: Interaction of nutrition and the immune response. Indian J Med 66:48-57, 1978.
  19. Miranda R, Saravia NG, Ackerman R, et al: Effect of maternal nutritional status on immunological substances in human colostrum and milk. Am J Clin Nutr 37(4):632-640, 1983.
  20. Robertson DM, Carlsson B, Coffman K, et al: Avidity of IgA antibody to Escherichia coli polysaccharide and diphtheria toxin in breast milk from Swedish and Pakistani mothers. Scand J Immunol 28:783-789, 1988.
  21. Stemberger B, Patton S: Relationship of size, intracellular lactation and time required for secretion of milk fat droplets. J Dairy Sci 64: 422-426, 1981.
  22. Bitman J, Wood L, Hamosh M, et al: Comparison of the lipid composition of breast milk from mothers of term and preterm infants. Am J Clin Nutr 38(2):300-312, 1983.
  23. Ruegg M, Blanc B: The fat globule size distribution in human milk. Biochim Biophys Acta 666:7-14, 1981.
  24. Simonin C, Ruegg M, Sidiropoulos D: Comparison of the fat content and fat globule size distribution of breast milk from mothers delivering term and preterm. Am J Clin Nutr 40:820-826, 1984.
  25. Innis SM: Essential fatty acids in growth and development. Prog Lipid Res 30:39-103, 1991.
  26. Hamosh M: Long chain polyunsaturated fatty acids in neonatal nutrition. J Am Coll Nutr 13:546-548, 1994. Editorial.
  27. Luukkainen P, Salo MK, Nikkari T: Changes in the fatty acid composition of preterm and term human milk from 1 week to 6 months of lactation. J Pediatr Gastroenterol Nutr 18 (3): 355-60, 1994.
  28. Holman RT, Johnson SB, Ogburn PL: Deficiency of essential fatty acids and membrane fluidity during pregnancy and lactation. Proc Natl Acad Sci U S A 88:4835-4839, 1991.
  29. Hytten FE: Clinical and chemical studies in human lactation: Variations in major constituents during a feeding. Br Med J 1:176, 1954.
  30. Macy IG, et al: Human milk studies. VII. Chemical analysis of milk representative of the entire first and last halves of the nursing period. Am J Dis Child 42:569, 1931.
  31. Insull W Jr, Hirsch J, James T, et al: The fatty acids of human milk. II. Alterations produced by manipulation of caloric balance and exchange of dietary fats. J Clin Invest 38:443-450, 1959.
  32. Prentice A, Jarjou LM, Drury PJ, et al: Breast-milk fatty acids of rural Gambian mothers: Effects of diet and maternal parity. J Pediatr Gastroenterol Nutr 8(4):486-490, 1989.
  33. Tyson J, Burchfield J, Sentance F, et al: Adaptation of feeding to a low fat yield in breast milk. Pediatrics 89(2):215-220, 1992.
  34. Michaelsen KF, Larsen PS, Thomsen BL, et al: The Copenhagen cohort study on infant nutrition and growth: Breastmilk intake, human milk macronutrient content, and influencing factors. Am J Clin Nutr 59:600-611, 1994.
  35. Dallman PR: Iron deficiency in the weanling: A nutritional problem on the way to resolution. Acta Paediatr Scand Suppl 323:59, 1986.
  36. Siimes MA, Salmenpera L, Perheentupa J, et al: Exclusive breast-feeding for 9 months: Risk of iron deficiency. J Pediatr 104:196-199, 1984.
  37. Ekstrand J, Spak CJ, Falch J, et al: Distribution of fluoride to human breast milk following intake of high doses of fluoride. Caries Res 18:93-95, 1984.
  38. Vuori E, Makinen SM, Kara R, et al: The effects of the dietary intakes of copper, iron, manganese, and zinc on the trace element content of human milk. Am J Clin Nutr 33:227-231, 1980.
  39. Gushurst CA, Mueller JA, Green JA, et al: Breast milk iodide: Reassessment in the 1980s. Pediatrics 73:354-359, 1984.
  40. Mannan S, Picciano MF: Influence of maternal selenium status on human milk selenium concentration and glutathione peroxidase activity. Am J Clin Nutr 46:95-100, 1987.
  41. Goldman AS: The immune system of human milk: Antimicrobial, antiinflammatory, and immunomodulating properties. Pediatr Infect Dis J 12:664-672, 1993.
  42. Goldman AS, Chheda S, Keeney SE, et al: Immunologic protection of the premature newborn by human milk. Semin Perinatol 18:495-501, 1994.
  43. Stromquist M, Folk P, Bergstrom S, et al: Human milk k-casein and inhibition of Helicobacter pylori adhesion to human gastric mucosa. J Pediatr Gastroenterol Nutr 21: 288-296, 1995.
  44. Hamosh M: Enzymes in human milk: Their role in nutrient digestion, gastrointestinal function and nutrition in infancy, in Lebenthal E (ed): Textbook of Gastroenterology and Nutrition in Infancy, ed 2. New York, Raven Press, 1989, pp 121-134.
  45. Goldman AS, Goldblum RM: Human milk: Immunologic-nutritional relationships. Ann N Y Acad Sci 587:236-245, 1990.
  46. Hamosh M, Pollock DR, Henderson TR, et al: Bacterial growth during short term storage of human milk (>15oC) is prevented by rapid lipolysis and only limited proteolysis. Pediatr Res 35:312A, 1994.
  47. Hamosh M, Ellis LA, Pollock DR, et al: Breast-feeding and the working mother: Effect of time and temperature of short term storage on proteolysis, lipolysis and bacterial growth in milk. Pediatrics 97:492-498, 1995.
  48. Hanson LA, et al: The secretory IgA system in the neonatal period. In Ciba Foundation Symposium 77: Perinatal Infections. Amsterdam, Excerpta Medica 187, 1990.
  49. Goldman AS, Thorpe LW, Goldblum RM, et al: Anti-inflammatory properties of human milk. Acta Paediatr Scand 75:698, 1986.
  50. Hanson LA, Soderstrom T, Brinton C, et al: Neonatal colonization with Escherichia coli and the ontogeny of the antibody response. Prog Allergy 33:40-52, 1983.
  51. Adderson EE, Johnston JM, Shakenford PG, et al: Development of the human antibody repertoire. Pediatr Res 32:257-263, 1992.
  52. Goldman AS, et al: Cytokines in human milk. Properties and potential effects. J Mammary Gland Biol Neoplasia. In press.
  53. Newburg DS, Newbauer SH: Carbohydrates of milk, in Jensen RG (ed): Handbook of Milk Composition. San Diego, Academic Press, 1995, pp. 273-349.
  54. Newburg DS, Linhardt RJ, Ampofo SA, et al: Human milk glycosaminoglycans inhibit HIV glycoprotein gp120 binding to its host cell CD4 receptor. J Nutr 125(3): 419-24; 1995.
  55. Lucas A, Cole TJ: Breast milk and neonatal necrotising enterocolitis. Lancet 336 (8730): 1519-23, 1990.
  56. Beaudry M, Dufour R, Marcoux S: Relation between infant feeding and infections during the first six months of life. J Pediatr 126(2): 191-7, 1995.
  57. Newburg DS: Do the binding properties of oligosaccharides in milk protect infants from gastrointestinal bacteria. J Nutr 1997. In press.
  58. Schroten H, Hanisch FG, Plogmann R, et al: Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction. Infect Immun 60(7): 2893-9, 1992.
  59. Hamosh M: Free fatty acids and monoglycerides: Antiinfective agents produced during the digestion of milk fat by the newborn. Adv Exp Biol 30:151-158, 1991.
  60. Isaacs CE, Thormar H: The role of milk derived antimicrobial lipids as antiviral and antibacterial agents. Adv Exp Med 30:159, 1991.
  61. Koldovsky O: Hormones in milk: Their possible physiological significance for the neonate, in Lebenthal E (ed): Textbook of Gastroenterology and Nutrition in Infancy, ed 2. New York, Raven Press, pp 97-119, 1989.
  62. Grosvenor CE, Picciano MF, Baumrucker CR: Hormones and growth factors in milk. Endocrine Revs 14:710, 1992.
  63. Ellis LA, Picciano MF: Milkborne hormones: Regulators of development in neonates. Nutr Today 27:6, 1992.
  64. Donovan SM, Odle J: Growth factors in milk as mediators of infant development. Annu Rev Nutr 14:147, 1994.
  65. Ellis LA, Mastno AM, Picciano MF, et al: Do milk-borne cytokines and hormones influence neonatal immune cell function? J Nutr 1997. In press.
  66. Hamosh M: Enzymes in human milk: Characteristic and physiologic functions, in Jensen RG (ed): Handbook of Milk Composition. San Diego, Academic Press, 1995. In press.
  67. Udall JN, Dixon M, Newman AP, et al: Liver disease in alpha-1-antitrypsin deficiency: A retrospective analysis of the influence of early breast vs. bottle-feeding. JAMA 253:2679, 1985.
  68. Jones JB, Mehta NR, Hamosh M: alpha-Amylase in preterm human milk. J Pediatr Gastroenterol Nutr 1:43-48, 1982.
  69. Bechamp A: Sur la zymase du lait de femme. CR Acad Sci 96:1508-1510, 1883.
  70. Hanafy MM, El-Khateeb S, Guirgis S, et al: Diastase in human milk. Alexandria Med J 17:299-305, 1971.
  71. Lebenthal E, Lee PC: Development of functional response in human exocrine pancreas. Pediatrics 66:556-560, 1980.
  72. Barbezat G, Hansen JDL: The exocrine pancreas and protein-calorie malnutrition. Pediatrics 42:77-92, 1968.
  73. Danus O, Urbina AM, Valenzuela I, et al: The effect of refeeding on pancreatic exocrine function in marasmic infants. J Pediatr 77(2):334-7, 1970.
  74. Watson RR, Tye JG, McMurray DN, et al: Pancreatic and salivary amylase in undernourished Colombian children. Am J Clin Nutr 30(4):599-604, 1977.
  75. Sauniere JF, Sarles H: Exocrine pancreatic function and protein-calorie malnutrition in Dakar and Abidjan (West Africa) silent pancreatic insufficiency. Am J Clin Nutr 48:1233-1238, 1988.
  76. Mehta NR, Jones JB, Hamosh M: Lipases in human milk: Ontogeny and physiologic significance. J Pediatr Gastroenterol Nutr 1:317-326, 1982.
  77. Alemi B, Hamosh M, Scanlon JW, et al: Fat digestion in very low birth weight infants: Effect of addition of human milk to low birth weight formula. Pediatrics 68(4):484-489, 1981.
  78. Williamson S, Finucane E, Ellis H, et al: Effect of heat treatment of human milk on absorption of nitrogen, fat, sodium, calcium and phosphorus by preterm infants. Arch Dis Child 53(7):555-563, 1978.
  79. Brennen J: Carnitine metabolism and function. Physiol Rev 63:1420, 1983.
  80. Gaull GE: Taurine in pediatric nutrition: Review and update. Pediatrics 83:433, 1989.
  81. Uauy R: Dietary nucleotides and requirements in early life, in Lebenthal E (ed): Textbook of Gastroenterology and Nutrition in Infancy, ed 2. New York, Raven Press, 1989, pp 265-280.
  82. Hamosh M: Should infant formulas be supplemented with bioactive components and conditionally essential nutrients present in milk? J Nutr 1997. In press.
  83. Hamosh M, Hong MH, Hamosh P: beta-Casomorphins: milk-beta-casein derived opioid peptides, in Lebenthal E (ed): Textbook of Gastroentorology and Nutrition in Infancy, ed 2. New York, Raven Press, 1989, pp 143-150.
  84. Hamosh M, Hamosh P: Differences in composition of preterm, term and weaning milk, in Xanthou M (ed): New Aspects of Nutrition in Infancy and Prematurity. Amsterdam, Elsevier, 1987, pp 129-141.
  85. Schanler RJ, Hurst NM: Human milk for the hospitalized preterm infant. Seminar Perinatol 18:476, 1994.
  86. Koletzko S, Sherman P, Corey M, et al: Role of infant feeding practices in development of Crohn's disease in childhood. Br Med J 298(6688):1617-1618, 1989.
  87. Mayer EJ, Hamman RF, Gay EC, et al: Reduced risk of IDDM among breast fed children. The Colorado IDDM Registry. Diabetes 37(12):1625-1632, 1988.
  88. Davis MK, Savitz DA, Grauford B: Infant feeding and childhood cancer. Lancet 2(8607):365-368, 1988.
  89. Lucas A, Morley R, Cole TJ, et al: Breast milk and subsequent intelligence quotient in children born preterm. Lancet 339(8788):261-264, 1992.
  90. Lucas A, Morley R, Cole TJ, et al: A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child 70(2):F141-F146, 1994.
  91. Rogan WJ, Gladen BC: Breast-feeding and cognitive development. Early Hum Devel 31(3):181-193, 1993.
  92. Hamosh M: Lipid metabolism in pediatric nutrition. Pediatr Clin North Am 42:839-959, 1995.


Dr. Hamosh is a professor of pediatrics and chief, Division of Developmental Biology and Nutrition, Department of Pediatrics, at Georgetown University Medical Center in Washington, D.C.


Hamosh M. Breastfeeding: Unraveling the Mysteries of Mother's Milk. MedGenMed 1(1), 1999. [formerly published in Medscape Women's Health eJournal 1(5), 1996]. Available at: http://www.medscape.com/viewarticle/408813.