Stages of Lactogenesis

Full alveolar development and maturation of the breast must await the hormones of pregnancy—progesterone, prolactin, and human placental lactogen (hPL)—for completion of the developmental process at delivery. This is termed lactogenesis stage I. By midpregnancy, the gland is competent to secrete milk (colostrum), although full function is not attained until the tissues are released from the inhibition of high levels of circulating progesterone.

Lactogenesis stage II occurs as the progesterone levels fall after delivery of the placenta, during the subsequent 7 days. During the first 2 to 4 days after delivery, incremental secretion of colostrum occurs (50 to 400 mL/day). Until lactogenesis stage II has fully developed, the breasts secrete colostrum, which is very different from mature milk in volume and constituents. Colostrum has more protein, especially secretory immunoglobulins, and more lactose; it also has a lower fat content than mature milk. Prolactin and glucocorticoids play important promoter roles in this stage of development.

At 2 to 5 days postpartum, a dramatic increase occurs in mammary blood flow and oxygen/glucose uptake by the breast. The secretion of milk is copious, 500 to 700 mL/day when “the milk comes in.” This is the most common time for engorgement if the breasts are not drained by efficient, frequent nursing.

After lactogenesis stage II, which occurs from 3 to 7 days postpartum, lactation enters an indefinite period of milk production formerly called galactopoiesis, now termed lactogenesis stage III . The duration of this stage is dependent on the continued production of breast milk and the efficient transfer of breast milk to the infant. Prolactin appears to be the single most important galactopoietic hormone because selective inhibition of prolactin secretion by bromocriptine disrupts lactogenesis; oxytocin appears to be the major galactokinetic hormone. Stimulation of the nipple and areola and infant behavioral cues cause a reflex contraction of the myoepithelial cells that surround the alveoli and trigger ejection of milk from the breast.

The final stage of lactation, lactogenesis stage IV, is involution and cessation of breastfeeding. As the frequency of breastfeeding is reduced to less than six episodes in 24 hours, and the produced milk volume is less than 400 mL in 24 hours, prolactin levels fall in proportion to the frequency of nipple stimulation, which ultimately leads to a total cessation of milk production. After 24 to 48 hours of no transfer of breast milk to the infant, increasing intraductal pressure and production of lactation inhibitory factor from the alveolar epithelium appear to initiate apoptosis of the secretory epithelial cells and proteolytic degradation of the basement membrane. Lactation inhibitory factor is a protein secreted in the milk, and its increasing concentration in the absence of milk drainage appears to decrease milk production by the alveolar cells. It counterbalances pressures to increase milk supply (i.e., increased frequency of nursing) and allows for the day-to-day adjustment in infant demands.

Endocrinology of Lactogenesis

Prolactin is the major hormone that promotes milk production, and thyroid hormones selectively enhance the secretion of lactalbumin. Cortisol, insulin, parathyroid hormone, and growth hormone are supportive metabolic hormones in the production of carbohydrates and lipids in breast milk. Ovarian hormones are not required for the maintenance of established milk production and are suppressed by high levels of prolactin.

The alveolar cell is the principal site for the production of milk. Neville describes five pathways for milk synthesis and secretion in the mammary alveolus, including four major transcellular and one paracellular pathway: (1) exocytosis (merocrine secretion) of milk protein and lactose in Golgi-derived secretory vesicles; (2) milk fat secretion via milk fat globules (apocrine secretion); (3) secretion of ions and water across the apical membrane; (4) pinocytosis-exocytosis of immunoglobulins; and (5) a paracellular pathway for plasma components and leukocytes. During lactation, as opposed to during pregnancy, very few of the constituents of breast milk are transferred directly from maternal blood. The junctions between cells, also known as tight junctions, are closed. As weaning occurs, the tight junctions are released and sodium and other minerals easily cross to the milk, which changes the taste of the milk. The change in taste may affect the interest of the infant to continue to breastfeed.

The majority of milk is produced de novo by the breast, rather than by direct absorption from the maternal gut or from manufacture by maternal organs such as the liver, kidneys, and so on. The substrates for milk production are primarily absorbed from the maternal gut or are produced in elemental form by the maternal liver. Glucose is the major substrate for milk production. It serves as the main source of energy for other reactions and is a critical source of carbon. The synthesis of fat from carbohydrates plays a predominant role in fat production in human milk, whereas proteins are built from free amino acids derived from plasma.

A sizable proportion of breast milk is produced during the nursing episode. In order to supply the substrates for milk production, blood flow increases to the mammary glands (20% to 40%), GI tract, and liver. Cardiac output is increased by 10% to 20% during a nursing episode. The vasodilation of the regional vascular beds is under the control of the autonomic nervous system, and oxytocin may play a critical role in directing the regional distribution of maternal cardiac output through an autonomic, parasympathetic action.

Given that milk is produced during the nursing episode, variation in content during a feed is expected. During a feeding episode, the lipid content of milk rises by more than twofold to threefold (1% to 5%) with a corresponding 5% fall in lactose concentration. The protein content remains relatively constant. At the extreme, there can be a 30% to 40% difference in the volume obtained from each breast. Likewise, intraindividual variations have been observed in lipid and lactose concentrations.

The rising lipid content during a feed has practical implications in breastfeeding management. If a woman limits feedings to less than 4 minutes but nurses more frequently, the calorie density of the milk is lower, and the infant’s hunger may not be satiated. As a result, the infant wishes to feed sooner, and the frequency of nursing accelerates; this stimulates more milk production and creates a scenario of a hungry infant despite apparent good volume and milk transfer. Lengthening the nursing episode or using one breast for each nursing episode often solves the problem.

The volume and concentration of constituents also vary during the day. The volume per feed increases by 10% to 15% in the late afternoon and evening. Nitrogen content peaks in the late afternoon and falls to a nadir at 5 : 00 am . Fat concentrations peak in the early morning and reach a nadir at 9 : 00 pm . Lactose levels stay relatively stable throughout the day. The variation in milk volume and content in working women who nurse only when at home has not been studied. The variation in volume and content is preserved if the woman pumps breast milk adequately (every 2 to 3 hours) during the day.

Does diet affect the volume and constitution of breast milk? For the average American woman with the range of diets from teenagers to mature, health-conscious adults, the answer is no . No convincing evidence suggests that the macronutrients in breast milk—protein, fats, and carbohydrates—vary across the usual range of American diets, although volume may vary in the extremes. In developing countries where starvation is widespread and daily calorie intake is less than 1600 kcal/day during prepregnancy and pregnancy, the mother’s milk volume and its caloric density are only minimally decreased (5% to 10%) in underweight breastfeeding women. In a controlled experiment, well-nourished European women reduced their calorie intake by 33% for 1 week. Milk volume was not reduced when the diet was maintained at greater than 1500 kcal/day. If the daily energy intake was less than 1500 kcal, milk volume was reduced by 15%. Moderate dieting and weight loss postpartum (4.5 lb/month) are not associated with changes in milk volume, nor does aerobic exercise have any adverse effect.

In the first year of life, the infant undergoes tremendous growth: infants double their birthweight in 180 days. Infants fed artificial breast milk (formula) lose up to 5% of their birthweight during the first week of life, and breast milk–fed infants lose about 7% of their birthweight. A maximum weight loss of 10% of birthweight is tolerated in the first week of life in breast-fed infants. If this threshold is exceeded, the breastfeeding dyad needs immediate intervention by a trained health care provider. Although supplementation with donor breast milk or artificial breast milk may be a necessary part of the intervention, the key focus of intervention is establishing good breast milk transfer by ensuring adequate production, correct nursing behavior, correct latch-on, and adequate frequency. Once lactogenesis stage III occurs, “the milk has come in”; the term infant will gain about 0.75 to 1 oz/day with adequate breast milk transfer. By 14 days, the breast-fed infant should have returned to its birthweight.

Food intake and energy needs are not constant. The infant’s need for energy and fluids can vary daily or weekly because of growth spurts; greater activity; immunologic challenges, such as when fighting an illness; or with greater fluid losses, as in hot weather. Mammals have developed an extremely efficient mechanism to adjust milk supply within 24 to 48 hours, depending on demand, via oxytocin and the let-down reflex ( Fig. 24-3 ) and prolactin production. The prolactin and oxytocin travel to their target cells: prolactin goes to the alveolar epithelium in the breast, and oxytocin goes to the myoepithelial cells that shroud the alveolar epithelium. In lactating women, baseline prolactin levels are 200 ng/mL at delivery, 75 ng/mL between 10 and 90 days postpartum, 50 ng/mL between 90 and 180 days postpartum, and 35 ng/mL after 180 days postpartum. Maternal serum prolactin levels rise by 80% to 150% of baseline levels within seconds of nipple stimulation. As long as nursing frequency is maintained at more than eight episodes a day for 10 to 20 minutes with each episode, the serum prolactin levels will suppress the luteinizing hormone (LH) surges and ovarian function. Serum oxytocin levels also rise with nipple stimulation. However, the oxytocin response is much more affected by operant conditioning, and its response may precede the rise in prolactin levels. The maternal cerebrum is influenced by exposure to nursing cues and to the influences of nipple stimulation. The cerebrum either stimulates or inhibits the hypothalamus to increase or decrease the production of prolactin inhibitory factor (dopamine) and, subsequently, this drives the release of oxytocin from the posterior pituitary. Cerebral influences have a lesser effect on the release of prolactin. Positive sights, sounds, or smells related to nursing often stimulate the production of oxytocin, which in turn causes the myoepithelial cells to contact and allows milk to leak from the breasts. This observation is a good clinical clue to indicate an uninhibited let-down reflex.

Oxytocin and the let-down reflex. The major reflex includes feedback stimulation from the nipple/areola to the hypothalamus to increase/decrease the release of oxytocin from the posterior pituitary and prolactin inhibitor factor (PIF, dopamine). The PIF affects the release of prolactin, which increases milk production; oxytocin causes milk ejection, and the release of both hormones is affected by positive or negative influences from the upper central nervous system (CNS). Oxytocin has three different target sites: the gastrointestinal (GI) tract (motility), uterus (contractions), and the upper CNS (mother-infant bonding). Oral stimulation in the infant initiates oxytocin release to improve GI function and maternal-infant bonding.

In a classic series of experiments in 1958, Newton and Egli demonstrated the power of noxious influences to inhibit the release of oxytocin and reduce milk transfer to the infant. The baseline milk production per feed was measured in controlled situations at about 160 g per feed. During a consecutive feed, a noxious event (i.e., saline injection) was administered during the feed. The amount of milk produced was cut in half, to 80 to 100 g per feed. Subsequently, the milk production was measured in a trial in which a noxious event was administered and intranasal oxytocin was given concomitantly. The milk production was restored to almost 90% of baseline production, 130 to 140 g. A wide variety of noxious events elicited the same decrease in milk production, including placing the mother’s feet in ice water, applying electric shocks to her toes, having her trace shapes while looking only through a mirror, or requiring her to proofread a document in a timed fashion. These observations have important implications concerning the management of breastfeeding. Pain, anxiety, and insecurity may be hidden reasons for breastfeeding failure through inhibition of the let-down reflex.

In contrast, the playing of a soothing motivational/educational audio tape to women who were pumping milk for their premature infants has improved milk yields. These observations have been confirmed by measuring the inhibition of oxytocin release by psychological stress. The positive and negative influences of the cerebrum are further highlighted by the observation that 75% of women who had a positive attitude during pregnancy were likely to be successful at breastfeeding. In contrast, 75% of women who had a negative attitude during pregnancy had an unsuccessful breastfeeding experience. When the mother’s attitude was good or very good and family was present, the exclusive breastfeeding rate was 20% at 6 months; if the mother’s attitude was fair, the breastfeeding rate at 6 months was 5%.

Oxytocin has additional target cells in the mother (see Fig. 24-3 ), and the effect of oxytocin on uterine activity is well known. Uterine involution is enhanced with breastfeeding. Animal and human research suggests that oxytocin is a neurohormone associated with an anti–fight/flight response in the autonomic nervous system, better toleration of stress by the mother, and improved maternal-infant bonding.

In addition to the antistress effect, surges in oxytocin levels are associated with the release of GI hormones and increased GI motility. In the mother, these actions enhance the absorption of substrates necessary for lactogenesis, and a growing body of knowledge indicates similar associations with oxytocin surges in infants. Skin-to-skin contact and the oral stimulation of nursing stimulate a parasympathetic, anti–fight/flight response in the infant. So-called kangaroo care of premature newborns, with skin-to-skin contact, is associated with a physiologically stable state, improved stress responses, and improved weight gain. Oxytocin appears to mediate this response. Breastfeeding is associated with far more skin-to-skin contact and maternal behaviors than bottle feeding.

Whereas the central nervous system (CNS) locus for imprinting is unknown, imprinting immediately after birth is an important predictor of breastfeeding success. The survival of lambs depends on nursing within an hour after birth. If the lamb has not nursed during the critical period, maternal-infant bonding becomes dysfunctional, and the lamb suffers failure to thrive. In humans, the consequences are not nearly as drastic. Several trials with random assignment of subjects to early nursing (delivery room) or late nursing (2 hours after birth) demonstrated a 50% to 100% higher number of breastfeeding mothers at 2 to 4 months postpartum among those who had nursed in the delivery room. One of the keys to obstetric management is have the mother nurse her newborn in the delivery room within 30 to 60 minutes of birth.

Milk Transfer

Milk transfer to the infant is a key physiologic principle in lactation. The initial step of milk transfer is a good latch-on. With light tactile stimulation of the infant’s cheek and lateral angle of the mouth, the infant reflexively turns its head and opens its mouth, as in a yawn ( Fig. 24-4 ). The nipple is tilted slightly downward using a “C-hold,” or palmar grasp. In this hand position, the fingers support the breast from underneath and the thumb lightly grasps the upper surface 1 to 2 cm above the areola-breast line. The infant is brought firmly to the breast by the supporting arm, being careful not to push the back of the baby’s head ( Fig. 24-5 ). The nipple and areola are drawn into the mouth as far as the areola-breast line. The posterior areola may be less visible than the anterior areola, and the lower lip of the infant is often curled out. The infant’s lower gum lightly fixes over the lactiferous sinuses.

The latch-on reflex.

The successful C-hold with appropriate latch-on.

The mechanics of normal breastfeeding behaviors relative to oropharyngeal movements and intraoral pressures have been eloquently demonstrated by transbuccal ultrasound. A slight negative pressure exerted by the infant’s oropharynx and mouth holds the length of the teat and breast in place and reduces the “work” to refill the lactiferous sinuses after they are drained. The milk is extracted not by negative pressure but by a peristaltic wave from the tip to the base of the tongue. There is no stroking or friction, and little in-and-out motion of the teat is apparent; the action is more undulating. The buccal mucosa and tongue mold around the teat, leaving no space.

The peristaltic movement of the infant’s tongue is most frequent in the first 3 minutes of a nursing episode; the mean latency from latch-on to milk ejection is 2.2 minutes. After milk flow is established, the frequency of sucking falls to a much slower rate. The change in cadence is recognizable as suck-suck-swallow-breath. Audible swallowing of milk is a good sign of milk transfer. At the start of a feeding, the infant obtains 0.10 to 0.20 mL per suck. As infants learn how to suck, they become more efficient at obtaining more milk in a shorter period of time. From 80% to 90% of the milk is obtained in the first 5 minutes the infant nurses on each breast, but the fat-rich and calorie-dense hind milk is obtained in the remainder of the time sucking at each breast, usually less than 20 minutes total. A bottle-feeding infant sucks steadily in a linear fashion and receives about 80% of the artificial breast milk in the first 10 minutes.

Sucking on a bottle is mechanically very different from nursing on the human teat ( Figs. 24-6 and 24-7 ). The relatively inflexible artificial nipple resists the milking motion of the infant’s tongue and mouth. The diameter of the artificial nipple expands during a suck, whereas the human teat collapses during the milk flow. The infant who is sucking on a bottle learns to generate strong negative pressures (>100 mm Hg) in order to suck the milk out of the bottle. Because rapid flow from the bottle can gag the infant, he or she quickly learns to use the tongue to regulate flow. When the infant who has learned to bottle feed is put to the breast, the stopper function of the tongue may abrade the tip of the nipple and force it out of the infant’s mouth. The efficiency of milk transfer falls drastically, and the hungry infant becomes frustrated and angry. A similar rejection may occur 4 to 8 weeks postpartum, when the exclusively breastfeeding infant is given a bottle in preparation for the mother’s return to work.

The mechanics of breastfeeding.

The mechanics of bottle feeding.

Milk transfer is made more efficient by proper positioning of the infant to the breast, which places the infant and mother chest-to-chest. The infant’s ear, shoulder, and hip are in line. The most common maternal positions are the cradle hold, chest to-chest, side-lying, or the football hold ( Figs. 24-8 and 24-9 ). Each has its advantages. Rotating positions for nursing allows improved drainage of different lobules, which is important in the management of a “plugged” duct or mastitis. Maternal comfort and convenience are the major reasons for changing nursing positions; the football hold and side-lying positions are more comfortable when the mother has an abdominal incision.

Side-lying nursing.

The football hold.

The neonate should be fed every 2 to 3 hours or 8 to 12 times a day on demand. One of the important educational keys is for the mother to recognize the signs of a hungry baby before the baby is crying, angry, or stressed. The signs include lip smacking, hand movement to the mouth, restlessness, and vocalizations.

Baseline prolactin levels appear to be the major determinant of the maternal hormonal state during lactation, a state of high prolactin and low estrogen and progesterone levels. As the frequency of nursing decreases below eight in 24 hours, the baseline prolactin levels drop below a level at which ovulation is suppressed (35 to 50 ng/mL), LH levels rise, and menstrual cycling is initiated. The intensity (adjusted odds ratio [OR]) of factors that initiate the onset of menses are the duration of sucking episodes less than 7 minutes (OR 2.4), night feedings less than four per 24 hours (OR 2.3), maternal age 15 to 24 years (OR 2.1), maternal age 25 to 34 years (OR 1.7), and day feedings less than seven per 24 hours (OR 1.6). In women who feed their infants exclusively artificial breast milk, serum prolactin levels drop to prepregnant levels (8 to 14 ng/mL) within days. In summary, the total number of nursing episodes per day (more than eight per 24 hours) and night nursings are critical to the successful management of breastfeeding.

One of the major determinants of nursing frequency is the introduction of substitute nutriment sources for the infant, artificial breast milk, or solids. Breast milk has the nutritional content to satisfy the growth needs of the infant for at least 6 months postpartum. In the first 6 months, feeding with artificial breast milk (i.e., formula) affects the physiology of successful lactation in three ways: (1) it reduces proportionally the nutriment requirements from breast milk; (2) it increases the gastric emptying time (digestion is slower than with breast milk), with a subsequent decrease in frequency of nursing episodes; and (3) it reduces the efficiency of nursing from use of an opposing sucking technique on the artificial nipple.

Starting the infant on solid foods (e.g., eggs, cereals, pureed food) has a similar effect on the hormonal milieu of the lactating woman, and one of the errors in Western child care is the early, forced introduction of solids. In most cases, the infant’s gut is filled with slowly digesting food with less nutritional value than breast milk, the long-term result of which may be childhood and adolescent obesity. The most logical time to start solid food substitution is when the infant has reached the neurologic maturity to grasp and bring food to its mouth from its mother’s plate, which usually occurs at about 6 months. As the infant matures, his or her ability to feed improves, and the proportion of the diet supplied by solid food gradually increases.

The failure to develop good milk transfer is the major cause of lactation failure and breast pain, especially in the neonatal period. Inhibition of the let-down reflex and failure to empty the breasts completely leads to ductal distension and parenchymal swelling from extravascular fluid. This is termed engorgement, and it compromises the mechanics of nursing ( Fig. 24-10 ); alveolar distension reduces secretion of milk by the alveolar cells. Without adequate transfer of milk to the infant, lactation is doomed to fail. Distension of the alveoli by retained milk causes a rapid (6 to 12 hours) decrease in milk secretion and enzyme activity by the alveolar epithelium. The decreased production of milk is explained by pressure inhibition and by an inhibitor secreted in breast milk. Distension of the alveoli inhibits secretion directly, rather than indirectly, by a decrease in nutriment or hormonal access.

Breastfeeding and engorgement. The firm, swollen breast parenchyma pushes the newborn’s face away, and she is unable to pull the teat into her mouth. Her tongue abrades the tip of the nipple.

Overview

The composition of mature human milk is very different from artificial breast milk (formula). Most artificial breast milk products use bovine milk or soybean constituents as a substrate. Minerals, vitamins, proteins, carbohydrates, and fats are added to pasteurized bovine milk for perceived nutritional needs, as well as marketing aims, to make a product that will successfully compete with human breast milk. For example, human breast milk appears “thinner” than bovine milk. Artificial breast milk manufacturers add constituents (e.g., palm- or coconut-based oils) to make artificial breast milk appear rich and creamy, thereby creating a product that is more easily marketed to the American public.

Extensive research describes the unique composition of human milk. The infant formula industry has produced even greater volumes of data concerning their attempts to exactly reproduce human milk. In 1980, the U.S. Congress passed the Infant Formula Act (with revisions in 1985) as the result of severe health consequences when artificial breast milk failed to include key vitamins and minerals in new formula compositions. This law now requires that all formulas for artificial breast milk contain minimum amounts of essential nutrients, vitamins, and minerals. Although life-threatening omissions are unlikely, current formulas have major differences in the total quantities and qualities of proteins, carbohydrates, minerals, vitamins, and fats when compared with human milk. The reader is reminded that the recommended daily allowance (RDA) is the amount needed to prevent a deficiency disease, not the amount needed for the best health.

Breast milk promotes optimal somatic growth and metabolic competence. Human breast milk has evolved to ensure the most efficient digestion by the human infant, which is not the case with bovine or soybean-derived formulas. Gastric emptying is faster in neonates fed breast milk versus formula, 1 to 2 hours versus 3 to 4 hours, respectively. The greater speed of digestion with breast milk relates to differences in casein/whey protein ratio, fatty acid content, fatty acid attachment to the glycerol backbone, and presence of GI enzymes and GI hormones to facilitate digestion, motility, and function. Bovine formulas contain only limited and degraded hormones and enzymes appropriate for calves, and none of these important constituents is found in formulas that use a soybean base. In addition, the bioavailability of naturally supplied vitamins and minerals in breast milk is 20% to 50% higher than that of the vitamins and minerals added to artificial breast milk.

The nutritional differences between formula and human milk are reflected in differences in the growth patterns of infants who are exclusively breastfed for 4 to 6 months and infants who are fed artificial breast milk. In general, breast-fed infants have faster linear and head growth, whereas formula-fed infants tend to have greater weight gain and fat deposition. The greater deposition in fat may relate in part to the earlier introduction of solid foods in the infants fed formula, a factor that has not been adequately controlled in current studies.

Regardless of the cause, formula has important adverse effects on the metabolic competence of the child, adolescent, and future adult ( Table 24-1 ). Since 2007, when the extensive evidence-based reviews were published by the Agency for Healthcare Research and Quality (AHRQ) —and after follow-up analysis by Ip and colleagues in 2009—these findings have been verified, proving a dose-response relationship and providing an improved understanding of the physiologic and endocrine causes for the benefits seen with prolonged breastfeeding.

Breastfeeding enhances cognitive development. Human breast milk has superior capacity to enhance the development of the infant’s brain and its integrative capacity through many defined and undefined differences between human breast milk and formula. The currently identified constituents of human breast milk that enhance integrative capacity include growth hormones, oligosaccharides, nucleotides, glycoproteins, and long-chain polyunsaturated fatty acids (LCPUFAs). In high-risk, premature neonates, human breast milk given by gavage enhances the infant’s later intelligence quotient (IQ) and performance on psychometric testing in a dose-dependent fashion after controlling for maternal intelligence, family education, and socioeconomic status. A recent large cohort study that compared very-low-birthweight infants demonstrated that for every 10 mL/kg/day increment of breast milk fed to these high-risk neonates, neurodevelopmental outcomes improved.

Although the effect is most dramatic among high-risk infants, smaller effects on IQ are seen in term infants (adjusted increment [95% CI], 3.16 points [2.35 to 3.98] vs. low birthweight infants, 5.18 points [3.59 to 6.77]). A population-based birth cohort was launched in 1982 in Pelotas, Brazil among 5914 neonates. Initiation, exclusivity, and duration of breastfeeding was recorded between 19 and 42 months. At 30 years of age, 3701 of the enrollees (68% follow-up) underwent ascertainment of their IQ, educational achievement, and family income. In the confounder-adjusted analysis, those who were breastfeed 12 months or more had higher IQ scores (+3.76; 95% CI, 2.20 to 5.33), more years of education (+0.91 years; 95% CI, 0.41 to 1.40), and higher monthly income than those who were breastfed for less than 1 month.

The information regarding breastfeeding, LCPUFAs, and improved intelligence has been powerful enough for formula companies to change their concoctions to include more LCPUFAs. However, just adding LCPUFAs does not change the other deficiencies in formula. Another recent example of neurodevelopmental enhancement with breastfeeding is the strong association found between breastfeeding and enhanced visual acuity. Conversely, infants fed LCPUFA-enhanced formula had similar deficiencies in high-grade foveal stereoacuity (adjusted OR, 2.5; 95% CI, 1.4 to 4.5), as did those infants fed standard formula.

Breastfeeding enhances infant responses to infection and reduces allergic disease. At birth, the fetus enters an unsterile world with a naïve and immature immune system. Full development of the immune system may take up to 6 years. Breast milk has a wide array of antiinfective properties that will support the developing immune system. The major mechanisms for the protective properties of breast milk include active leukocytes, antibodies, antibacterial products, competitive inhibition, enhancement of nonpathogenic commensal organisms, and suppression of proinflammatory immune responses.

A critical event in host resistance is the recognition of pathogenic agents in the environment and the production of an antigen-specific adaptive immune response. Breastfeeding provides a unique system to help the infant fight infection with an adaptive antigen-specific response. Through breast milk, the neonate takes advantage of maternal recognition of these infectious agents ( Fig. 24-11 ). This important mechanism was described by Slade and Schwartz. An antigen or infectious agent—such as a virus, bacterium, fungus, or protozoan—stimulates the activity of leukocytes in the GI or respiratory tract of the mother. Lymphocytes encoded with the antigen signature travel to the nearest lymph node and stimulate lymphoblasts to develop cytotoxic T cells, helper T cells, and plasma cells programmed to destroy the initiating antigen through phagocytosis or complement/immunoglobulins produced by the B cells. The response is amplified by the migration of committed helper lymphocytes to other sites of white blood cell production, the spleen and bone marrow, where they stimulate the production of antigen-specific committed white blood cells. Some of the committed, antigen-specific helper lymphocytes travel to the mucosa of the breast in the lactating mother. Plasma cells, which produce secretory immunoglobulin A (sIgA), constitute 50% to 80% of the leukocytes in the breast submucosa. They may migrate into the breast milk (macrophages) or may produce immunoglobulins (sIgA, IgG—lymphocytes or plasma cells). Both are uniquely programmed to fight the specific infectious agent that challenges the mother. Active leukocytes are completely eliminated by pasteurization (formula) and freezing (stored, pumped breast milk).

The adaptive immunology of the breast. IgG, immunoglobulin G; sIgA, secretory immunoglobulin A.

Immunoglobulins are a unique component of breast milk that are absent in artificial breast milk. In contrast to monomeric serum IgA, the secretory IgA (sIgA) in breast milk is dimeric or polymeric; polymerization improves transport across the maternal alveolar cells into the breast milk. The immunoglobulins in breast milk appear to be fully functional. The sIgA is produced locally by plasma cells and does not activate complement or promote opsonic complement subfragments. As a consequence, sIgA is not bactericidal. It appears that sIgA blocks the mucosal receptors (adhesins) on the infectious agent. The virulence of pathogens is related to their ability to use adhesins capable of interacting with complementary gut epithelial cell-surface receptors. When the antigen-specific sIgA attaches, the pathogen is effectively neutralized.

In the last 5 to 10 years, an increasing amount of research has focused on critical imprinting between neonatal gut flora and future immune responses. The neonate is an antigen-naïve organism whose adaptive response is delayed by a lack of exposure. In addition, the cytokine response to TOLL-like receptor (TLR) stimulation appears to be exaggerated, especially in the preterm infant in whom injury is partly cytokine mediated (i.e., periventricular leukomalacia, necrotizing enterocolitis, and bronchopulmonary dysplasia). The adaptive immune system takes between 4 and 8 days to develop an effective defense; the neonate bombarded by new antigens/organisms during the birth process must rely on an innate host defense system to provide an immediate but controlled response during the first critical 7 days of breastfeeding.

Human breast milk actively limits pathogenic microbes (e.g., Escherichia coli ) and promotes the growth of nonpathogenic, commensal microbes (e.g., Bifidobacterium bifidum and other species). One of the most important breast milk constituents in the innate host defense system are human-specific oligosaccharides. Oligosaccharides are indigestible complex carbohydrate structures that have a microbe (genus)-specific ability to bind to cell-surface receptors of the microbe. The unique oligosaccharide binding to the surface receptor blocks the binding of the microbe to the infant’s mucosal receptors, thereby limiting microbe virulence. On the other hand, human milk contains an oligosaccharide homologous to the infant’s mucosal receptors. The oligosaccharide-mucosal receptor com­plex allows specific attachment of Bifidobacterium species to the intestinal mucosa, further competitively inhibiting the attachment of pathogenic organisms.

A similar attachment of B. bifidum to dendritic cells, which interdigitate through the intestinal epithelial cells, allows for a critical modulation of the developing neonatal immune system. The interaction upregulates the antiinflammatory cytokine system—interleukin (IL)-10, soluble IL-1 receptor antagonist, and so on—and orchestrates the conversion of naive T-helper cells into a mature, balanced response. These early imprinting interactions may have profound effects on the incidence of inflammatory diseases in the adult, intrinsic bowel disease, asthma, rheumatoid arthritis, and perhaps cardiovascular diseases. In addition to the crosstalk between commensal gut bacteria and the immune system of the neonate, human colostrum contains large quantities of a soluble form of the bacterial pattern recognition receptor, cluster of differentiation 14 (sCD14). CD14 is a known modulator of host response to bacterial lipopolysaccharides (LPSs). In particular, CD14 binds to TLR-4 receptors and limits the binding of LPS from gram-negative rods. The failure to activate the TLR-4 receptor reduces the exaggerated immature cytokine response possible in neonates. Recent therapeutic interventions have used the immune-modulating qualities of the commensal bacteria–host interactions to successfully treat several important human diseases: necrotizing enterocolitis, inflammatory bowel disease, Clostridium difficile– associated colitis, acute gastroenteritis, and atopic dermatitis.

Known and unknown constituents of human breast milk inhibit the growth of and actively destroy pathogenic organisms; formula has none of these constituents. Certain vitamins and minerals are essential for the growth of pathogenic bacteria, and a major mechanism by which breast milk protects the infant is the competition for “essential” nutriments for pathogenic bacteria. Iron and vitamin B ₁₂ are two essential nutriments for pathogenic bacteria that have been studied relative to breast milk. Breast milk contains lactoferrin, an iron-binding glycoprotein, in large quantities (5.5 mg/mL in the colostrum to 1.5 mg/mL in mature milk); this is absent in artificial breast milk. The free-iron form of lactoferrin competes with siderophilic bacteria for ferric iron and thus disrupts the proliferation of these organisms. The binding of iron to lactoferrin also enhances iron absorption; less iron is required in breast milk in order to satisfy the iron needs of the infant. The antibacterial role of lactoferrin is more complex than simple competition for ferric iron. Lactoferrin causes a release of LPS molecules from the bacterial cell wall. This appears to sensitize the bacterial cell wall to attack by lysozyme, and lactoferrin and lysozyme work together to destroy the pathogenic organisms.

Table 24-2 describes the effects of breastfeeding on the adaptive and innate host defenses. The cause of sudden infant death syndrome (SIDS) is not clear, but a current theory includes an aberrant immune response.

The hormonal changes of lactation—low estrogen, low progesterone, and hyperprolactinemic amenorrhea—favor a reduction in maternal reproductive cancers, but the relationship is undefined, and the relationship between the maternal immune system and the mother’s experience with breastfeeding has not been adequately explored. However, in a dose-dependent fashion, breastfeeding reduces breast cancer per year of cumulative breastfeeding by 4.3% (95% CI, 2.9% to 5.8%). Likewise, breastfeeding for greater than 12 months in the mother’s lifetime reduces ovarian cancer (adjusted OR, 0.72; 95% CI, 0.54 to 0.97); conversely, exclusive feeding with formula is associated with an enhanced risk of ovarian cancer (adjusted OR, 1.39; 95% CI, 1.03 to 1.85).

Breastfeeding enhances mother-infant bonding and reduces poor social adaptation. The human newborn infant is born entirely dependent on the mother for transportation, food, warmth, and social conditioning. Survival depends on a unique bond between mother and infant to enhance maternal protective behaviors. Like all other mammals, humans have a critical imprinting period (0.5 to 1 hour) for the establishment of mother-infant bonding. The most visible manifestation of the new bond is the duration of breastfeeding. Numerous studies with random assignment of breastfeeding dyads to early (<1 hour) or later (>2 hours) initiation of breastfeeding demonstrate a significantly higher incidence of any breastfeeding or exclusive breastfeeding at 2 to 4 months after birth in those dyads who initiated breastfeeding early.

A 2007 review by Moore and colleagues in the Cochrane Database of Systematic Reviews supports the benefits of early skin-to-skin contact. Their conclusions from a review of 30 studies that involved 1925 mother-infant dyads were that early skin-to-skin contact was associated with babies who interacted more with their mothers, stayed warmer, and cried less. Babies were more likely to be breastfed, and to breastfeed longer, if they had early skin-to-skin contact. More recently, a study with random assignment of subjects to immediate skin-to-skin contact or not—with timing of first feeding being mother directed and independently recorded—suggested that early skin-to-skin contact was a better predictor of duration of exclusive breastfeeding than the timing of the first sucking episode. This observation complements the success of so-called kangaroo care in the performance of high-risk neonates in the neonatal intensive care unit (NICU).

Recent human studies based on robust animal data suggest that continued skin-to-skin contact and breastfeeding greatly affect the responsiveness to stress in the infant and mother. Experimental physiologic and psychological stressors produce measured stress-induced changes in adrenocorticotropic hor­mone and cortisol and in autonomic responses in breastfeeding women versus women feeding their infants formula exclusively. In keeping with numerous animal studies, the breastfeeding mothers had a significantly blunted response of the hypothalamic-pituitary-adrenal (HPA) axis, also known as “fight or flight response,” to the experimental stressors. A reciprocal relationship is apparent in the breastfeeding infant, who has greater parasympathetic tone and a blunted HPA-axis response compared with a similar infant fed formula. These observations may be partially explained by a decrease in skin-to-skin contact in infants fed formula. Whereas kangaroo care has a salutary effect on breastfeeding incidence, the positive effects on weight gain and the blunted stress response are independently associated with the amount of skin-to-skin contact.

The association between breastfeeding and better psychosocial outcomes has been the topic of much epidemiologic research over many decades. Critics have repeatedly pointed out the selection bias inherent with these studies. However, improved epidemiologic research design has confirmed the lifelong value for the breastfeeding dyad in subsequent stressful situations. Two powerful studies illustrate the risk of not breastfeeding. In the first study, Strathearn and colleagues explored whether breastfeeding was protective against maternal-perpetrated child maltreatment. The study design monitored prospectively 7223 Australian mother-infant pairs (identified at first prenatal visit) and followed them over a 15-year period after birth. The primary outcome was substantiated maltreatment reports by a governmental child protection agency. Maternally perpetrated substantiated abuse or neglect was identified in 313 pairs (4.3% of the cohort). The analysis adjusted for the 18 confounding variables, which included five sociodemographic variables; four prenatal behaviors/attitudes (i.e., substance abuse, anxiety, attitude toward pregnancy); four infant factors, including NICU admission; seven postnatal behaviors/attitudes (i.e., mother-infant separation, maternal stimulation/teaching the baby, maternal depression). The adjusted OR for maternal maltreatment cases among children fed exclusively formula was 2.2 (95% CI, 1.5 to 3.2) versus any breastfeeding, and it was 3.8 (95% CI, 2.1 to 7.0) versus exclusive breastfeeding for 4 months or longer.

In a second study, the response of the child was measured. Montgomery and colleagues used data collected in the 1970 British Cohort Study, in which subjects were followed for 10 years; 8958 (71%) had complete data and were used in the analysis. The study analyzed childhood anxiety associated with parental divorce or separation as reported by their teachers on an analog scale of 0 to 50 related to the question, “Was (the subject) worried and anxious about many things?” Exclusive feeding with formula, after adjustment for many factors, was associated with a dramatic increase in perceived childhood anxiety (adjusted OR, 8.8; 95% CI, 5.3 to 12.2), whereas breastfeeding at entry had no significant effect on childhood anxiety associated with divorce (adjusted OR, 1.3; 95% CI, −3.6 to 6.1).

Breastfeeding is cost effective for the family and society. The nonmedical costs of artificial breast milk (formula) feeding are considerably higher than for breastfeeding. The direct cost of artificial breast milk feeding includes the cost of the artificial formula (900 mL/day), bottles, and supplies. In eastern North Carolina (April 2015), the average retail cost of 900 mL of brand name prepared formula was about $8.00 daily ($2920 yearly); of brand name concentrate, about $5.50 daily ($2008 yearly); and of powdered formula, about $4.65 daily ($1697 yearly). Store brands cost about two thirds of the price of brand names. Special formulas—including soy-based, LCPUFA-enhanced, and hypoallergenic formulas—cost 50% to 200% more. A major indirect cost of artificial breast milk feeding is the environmental impact of large dairy herds to supply the bovine milk substrate and the mountains of packaging material discarded in landfills or incinerated.

Breastfeeding provides the right amount of a superior product at precisely the right time and at the right temperature. The nonmedical costs of breastfeeding include the cost of increased dietary calorie and protein needs ($2 to $3 daily), nursing bras and breast pads, and an increased number of diapers in the first 2 to 3 months. If a rented electric breast pump is used when the woman returns to work, the cost of breastfeeding will increase $2 to $4 per day.

Increase in acute medical diseases will manifest as increased costs of medical care for those families who choose to feed their infant artificial breast milk or formula. Among Medicaid populations in Colorado and California and in health maintenance organizations (HMOs) in Arizona, the medical cost of artificial breast milk feeding amounts to $350 to $600 per year per infant. Among patients who belonged to a large HMO in Tucson, Arizona, the excess yearly medical costs of 1000 never–breast-fed infants versus 1000 infants who were exclusively breastfed for at least 3 months was $331,041 ( Table 24-3 ).

TABLE 24-3

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