Breast milk and breastfeeding: history, physiology, breast milk and the premature baby (2023)

mamogenese

Knowing how the breast develops is important for understanding the physiological changes that occur with the onset of breastfeeding. Breast tissue begins to develop in the womb and undergoes the first of many developmental changes necessary for proper lactation. At a gestational age of 18-19 weeks, a spherical breast bud can be observed in the fetus. A rudimentary mammary duct system forms in the yolk, which is present from birth. After birth, the growth of the gland parallels that of the child until puberty. The following images show the normal anatomy of the mammary gland after pubertal development.^[7]

The normal breast consists of about 15 to 20 lobes of glandular tissue. These lobes are further divided into lobes that produce milk during and after pregnancy. Each lobe contains between 20 and 40 lobes. The milk produced in the lobes in each lobe empties into a milk duct. The milk ducts then merge into 5 to 10 main milk ducts, which then open into the nipple, allowing the baby to receive milk.

Kwabtypen 1-4

There are four types of lobes. Type 1 lobules form in the uterus and are present until puberty. Once puberty has begun, changes in the hormone levels of estrogen and progesterone during each menstrual cycle stimulate the type 1 lobes to produce new alveolar buds and evolve into the more mature type 2 lobes. After puberty is completed, no further changes occur in the female breast until pregnancy.

During pregnancy, circulating hormones cause a remodeling of the breast, with the lobes gradually increasing in number and size. Towards the end of pregnancy, the breast consists almost entirely of type 3 mammary glands. Once lactation begins, the mammary glands produce and secrete milk and are considered type 4 mammary glands. type 4 back to type 4. cessation of lactogenic hormone stimulation, as well as local autocrine signals resulting in apoptosis and tissue remodeling.

Lactogenese

In lactogenesis, the mammary gland develops the ability to secrete milk. Lactogenesis includes all the processes required to transform the mammary gland from its undifferentiated state in early pregnancy to its fully differentiated state some time after pregnancy. This fully differentiated state allows lactation to occur. The two stages of lactogenesis are discussed below.

Stage 1 occurs in mid-pregnancy when the mammary gland becomes competent to secrete milk. The concentrations of lactose, total protein and immunoglobulin increase in the secreted glandular fluid, while the sodium and chloride concentrations decrease. The gland is now differentiated enough to secrete milk, as evidenced by the fact that women in the second or third trimester often describe drops of colostrum from their nipples. However, high circulating levels of progesterone and estrogen keep milk secretion in check.

Phase 2 of lactogenesis occurs around the time of calving. It is defined as the appearance of copious lactation due to the rapid drop in progesterone secondary to the removal of the placenta, as well as the increase in prolactin, cortisol and insulin levels. The work of Haslam and Shyamala shows that progesterone receptors are lost in the breast tissue during lactation, reducing the inhibitory effect of circulating progesterone.^{[8, 9]}Citrate levels also increase during lactogenesis; this increase is considered a reliable marker of the second stage of lactogenesis.

The stages of lactation can be summarized as follows (adapted from Riordan and Auerbach, 1998).^[10]

mamogenese

Breast growth (breast) occurs. The size and weight of the breasts increase.

Lactogenese

• Stage 1 (mid-pregnancy): alveolar cells differentiate from secretory cells.

• Stage 2 (from day 2 or 3 to day 8 after birth): The tight connection of the alveolar cell closes. A profuse milk secretion begins. The breasts are full. Endocrine control turns into autocrine control (demand-supply).

Galactopoiesis (more than 9 days after birth to onset of involution)

The established secretion is preserved. Control of the autocrine system continues.

Involution (on average 40 days after last lactation)

Milk secretion decreases due to the accumulation of inhibitory peptides.

Breastfeeding

During the second phase of lactogenesis, the breast becomes capable of producing milk. For the synthesis and continuous secretion of breast milk, the mammary gland must receive hormonal signals. These signals, which are a direct response to stimulation of the nipple and areola (breasts), are then passed on to the central nervous system. This cyclic process of synthesis and secretion of milk is called lactation. Breastfeeding takes place with the help of two hormones, prolactin and oxytocin. Although prolactin and oxytocin act independently on different cell receptors, their combined actions are essential for successful lactation.

prolactin

• Prolactin is a polypeptide hormone synthesized by lactotrophic cells in the anterior pituitary gland. The binding of prolactin to receptors on mammary gland epithelial cells stimulates milk production. These receptors are downregulated during periods of elevated progesterone levels, such as during pregnancy. Once delivery has occurred and the placenta has been removed, progesterone levels drop and prolactin receptors are upregulated, allowing lactogenesis to occur.

• Research over the past few decades has led to a deeper understanding of the role of prolactin in the body. Prolactin-related knockout animal models support the critical role of prolactin in lactation and reproduction, suggesting that most prolactin target tissues are modulated rather than prolactin-dependent.^[11]

oxytocin

• The other major hormone involved in the milk ejection or ejection reflex is oxytocin, which stimulates the contraction of myoepithelial cells. When the newborn is placed on the breast and begins to suckle, oxytocin is released. The child stimulates the touch receptors located close to the nipple and areola, which then create impulses that activate the dorsal root ganglia via the intercostal nerves.^{[10, 12, 13]}These impulses travel through the spinal cord and create an afferent neural pathway to the paraventricular nuclei of the hypothalamus, where the pituitary gland synthesizes and secretes oxytocin. Stimulation of the nuclei causes oxytocin to be released from the pituitary stalk to the posterior pituitary lobe, where oxytocin is stored.

• Oxytocin is released when the baby's suckling creates afferent impulses that stimulate the posterior lobe of the pituitary gland. It is released in a pulsatile fashion into adjacent capillaries and travels to receptors on myoepithelial cells of the chest which, when bound to oxytocin, stimulate the cells to contract. This contraction of the myoepithelial cells that line the ducts of the breast causes milk to be ejected from the alveoli into the ducts, which then pass through a pore in the nipple into the baby's mouth.

Milk secretion is directly correlated with milk synthesis and the regulation of milk synthesis is quite efficient. Milk synthesis remains remarkably constant at about 800 ml/day. However, the actual volume of milk secreted can be adjusted according to the infant's needs by the feedback inhibitor of lactation (FIL), a local factor secreted into the milk; therefore, the rate of milk synthesis is related to the degree of emptiness or fullness of the breasts. The emptier breast produces milk faster than the fuller breast.

Milk production responds to the welfare state of mothers. Therefore, stress and fatigue negatively affect a woman's milk production. The mechanism of this effect is the negative regulation of milk synthesis with increased levels of dopamine, norepinephrine or both, inhibiting prolactin synthesis. Relaxation is the key to successful breastfeeding.

Biochemistry of breast milk.

Human milk is a unique, species-specific, complex nutrient fluid with immunological and growth-promoting properties. This unique fluid actually evolves to meet baby's changing needs as it grows and matures.^[14]Numerous pathways and cellular processes are involved in the synthesis and secretion of milk by the mammary gland (summarized in the figure below).

The processing and packaging of nutrients in breast milk changes over time as the recipient child ages. For example, early milk or colostrum has lower fat concentrations than mature milk, but higher protein and mineral concentrations (see image below). This relationship is reversed as the baby gets older.

Important biochemical points are discussed below.

In addition to the changes from colostrum to mature milk that reflect the needs of the developing newborn, there are variations within a given breastfeeding session. The first milk that the child ingests (before the milk) has a lower fat content. As the baby continues to breastfeed for the next few minutes, the fat content increases. It is believed that the latter milk promotes satiety in the child. Finally, daily variations in breast milk reflect the mother's diet and daily hormonal fluctuations.

Specific enzymes to aid digestion in newborns

Breast milk contains several enzymes; some are specific for milk biosynthesis in the mammary gland (e.g., lactose synthetase, fatty acid synthetase, thioesterase), while others are specific for the digestion of proteins, fats and carbohydrates that facilitate the infant's ability to break down and absorb food. It. human milk. Certain enzymes also serve as a transport medium for other substances, such as zinc, selenium and magnesium.

Three-dimensional structure of breast milk.

Under the microscope, it is truly amazing what breast milk looks like. Although it is a liquid, breast milk has a substantial structure in the form of compartmentalization. Nutrients and bioactive substances are stored in different compartments. The most elegant example of this structure is lipids, which at the time of secretion from the apical mammary epithelial cell are wrapped in the plasma membrane, thus becoming the milk fat globule. Certain proteins, growth factors and vitamins are also captured in this globule of milk fat and embedded in the membrane itself.

The membrane acts as a stabilizing interface between the watery components of the milk and the compartmentalized fat. This interface allows the controlled release of the lipolysis products and the transfer of polar materials to the whey (aqueous phase). The bipolar properties of the membrane are also necessary for the stability of the emulsion of the blood cells themselves; therefore, the structure of breast milk provides readily available fatty acids and cholesterol for micellar absorption in the small intestine.

Designer proteins, carbohydrates and fats for optimal brain development

Breast milk provides adequate amounts of protein (primarily alpha-lactalbumin and whey), carbohydrates (lactose), minerals, vitamins and fat for the term baby. Fats consist of cholesterol, triglycerides, short chain fatty acids and long chain polyunsaturated fatty acids (LCP). LCP fatty acids (18 to 22 carbons long) are required for brain and retinal development. Large amounts of LCP omega-6 and omega-3 fatty acids, primarily the 20-carbon arachidonic acid (AA) and the 22-carbon docosahexaenoic acids (DHA), are deposited in the developing brain and retina during prenatal growth and early postnatally .

An infant, especially a premature infant, may have a limited ability to synthesize optimal levels of AA and DHA from linoleic and linolenic acids. Therefore, these two fatty acids can be considered as essential fatty acids. Many infant formulas in the United States contain AA, DHA, or both. The amount of AA and DHA in breast milk varies depending on the mother's diet.^{[5, 14, 15, 16]}The unique mixture of fatty acids in breast milk has been linked to the development of innate and adaptive immune regulation.

Prior to routine formula fortification with DHA and AA, breastfed infants showed better visual acuity at 4 months of age than formula-fed infants, as well as slightly improved cognitive development.^[17]However, this is not a universal finding and some researchers continue to question the benefits of DHA and AA. However, a study of 5-year-old breastfed children whose mothers received a modest DHA supplement for up to four months postpartum showed a significant improvement in long-term care compared to children whose mothers did not receive DHA.^[18]

Preterm formulas have also been found to improve bone mineralization. Formula fed to very low birth weight (VLBW) preterm infants has been shown to support growth and development better than full term formula fed to this population.^[19]​

A study of maternal dietary manipulation of fatty acid concentration and neurological differences in breast milk found no difference in neurological outcomes, despite higher levels of AA and DHA in the supplemented maternal group.^[20]This finding supports a more global effect of breast milk compared to a single agent causing developmental differences.

It is not yet clear whether healthy, term infants benefit from the addition of DHA and AA to formula because they are able to convert highly LCP fatty acids into DHA and AA. Term babies who are sick and babies born prematurely are more likely to benefit from formulas fortified with DHA, AA, or both.

Rather than producing better vision or greater intelligence, breast milk may somehow protect the developing neonatal brain from injury or less than optimal development by providing necessary building materials and growth factors that work synergistically and not in isolation .

A study by Dallas et al. indicated that milk produced by women who gave birth to preterm infants demonstrates a high rate of protein breakdown by endogenous proteases, and researchers suggested that such breakdown may help alleviate the problems associated with the digestive system of immature preterm infants. babies could decrease.^[21]The study, which analyzed a total of 32 samples of term milk and 28 samples of preterm milk (from 8 mothers and 14 mothers, respectively), found that preterm milk has a significantly higher peptide content than term milk. Cleavage site analysis suggested that the plasmin protease is more active in preterm milk and that cytosolic aminopeptidase and carboxypeptidase B2 also degrade milk proteins.^[21]

Immunological properties of breast milk.

Knowledge about the immunological properties and effects of breast milk continues to grow. Breast milk is a rich source of immunoglobulins, lactoferrin, lysozymes, cytokines and many other immunological factors that provide both active and passive immunity to the infant. An extensive review, recommended by one of the pioneers in this field, Dr. Armand Goldman, appeared inbreastfeeding medicine(2007).^[22]Below are highlights of some of the many known immune properties and functions of breast milk.

Immunoglobulins from breast milk

Breast milk contains all the different antibodies (M, A, D, G, E), but secretory immunoglobulin A (sIgA) is the most common. Milk-derived sIgA is an important source of passive acquired immunity for the infant during the weeks prior to endogenous sIgA production. During this time of reduced intestinal immune function in newborns, the infant has limited defenses against ingested pathogens. Therefore, sIgA is an important protective factor against infection. This is especially true for preterm infants whose innate ability of the gut to produce its own sIgA is slower than that of full-term infants, and therefore the major source of sIgA in this population comes from breast milk.^[23]

Assuming that the mother and her infant, who are closely related, share a common flora, the antigenic specificity of the sIgA in the mother in her milk is directed against the same antigens in the newborn. Maternal immunoglobulin A (IgA) antibodies from the gut and respiratory immune surveillance systems are transported to the mammary gland via the blood and lymphatic circulation and eventually extruded into the milk as sIgA. The packaging of IgA with a secretory component unique to the mammary gland protects sIgA from stomach acids in the infant, allowing it to reach the small intestine intact.

Other immunological properties of breast milk

In addition to antibodies, breast milk has many other immunological factors that interact with the gut microbiome to improve gut health. Lactoferrin is the major protein in human milk whey and plays an important role in the innate response to infection with its various antimicrobial and anti-inflammatory properties. Lactoferrin also helps promote the growth of beneficial bacteria and reduce the colonization of pathogenic species.^[24]One of the ways it can do this is by binding to iron, which then prevents the growth of various iron-dependent pathogens from further proliferation. Lactoferrin has also been shown to inhibit microbial adhesion to host cells and to have direct cytotoxic effects against bacteria, viruses and fungi, particularly through the formation of lactoferricin, a potent cationic peptide with bactericidal activity that is formed during the digestion of lactoferrin.^[25]

Human milk oligosaccharides (HMOs) are the second most abundant component of human milk after lactose and lipids. It is believed that healthcare organizations directly influence the gut microbiome by acting as a prebiotic for specific beneficial bacteria and reducing the adhesion of pathogenic bacteria to the intestinal epithelium.^[25]The type and amount of HMO excreted in human milk are genetically predetermined, influenced by maternal and other factors, and are highly variable between mothers and between stages of lactation.^[26]

Human milk glycoproteins (HMGPs) are also an important immunological component of human milk and have inhibitory activity against a broad spectrum of pathogens. One of the most recognized HGPs are the mucins. Mucins are important components of the extracellular matrix involved in several functions, including protection of the epithelium against pathogenic infections, regulation of cell signaling and transcription.^[27]

Our understanding of the interactive effect of these bioactive components, the impact of the microbiota on gut function and development (and the role of human milk in that development) is only beginning to be well understood. These components clearly have profound effects on people's health throughout life, especially during childhood.^{[28, 29, 30, 23]}

leukocytes from breast milk

Maternal leukocytes in breast milk provide active immunity to the infant by directly combating pathogens via phagocytosis, by producing bioactive compounds, helping to develop the newborn's immune system, or by stimulating the microenvironment of the infant's digestive tract. child change.^[31]The lactation phase is accompanied by important changes in the composition of milk leukocytes. In a study by Trend et al., total leukocyte counts and concentrations of the different subsets varied at different times of lactation. Their results showed that the colostrum contained about 146,000 cells/ml; the amount decreased in transitional (8-12 days postpartum) and mature (26-30 days postpartum) milk to 27,500 and 23,650 cells/ml, respectively.^[32]

Passive immunity of the mother to the recipient child

In anticipation of the endogenous maturation of the infant's own immune system, several immunological and bioactive components of milk work synergistically to provide a mother-to-child passive immune support system in the first days and months after birth.^[33]Ingested milk passively immunizes the newborn. Numerous studies have clearly documented this scenario and its clinical benefit, demonstrating a reduced risk of gastrointestinal and respiratory infections, especially during the first year of life.^{[14, 22, 34]}

There is increasing evidence that these immune and bioactive substances prepare the neonatal immune and gastrointestinal systems for selective antigen recognition and the development of cellular signals. This may explain the reduced risk of intestinal and respiratory allergies in breastfed children, and the lower than expected risk of autoimmune diseases in the breastfed population. Direct effects are difficult to prove given the multifactorial nature of these diseases; Taken together, however, the data support the beneficial nature of breast milk for the developing child.

Bioactive properties of breast milk.

Breast milk also contains growth modulators, such as epidermal growth factor (EGF), nerve growth factor (NGF), insulin-like growth factors (IGFs), and interleukins (ILs). Transforming growth factor (TGF) alpha, TGF beta and granulocyte colony stimulating factor (G-CSF) are also found in breast milk. These growth modulators are produced by mammary gland epithelial cells or by activated macrophages, lymphocytes (mainly T cells) or neutrophils in milk. Higher concentrations of EGF and TGF-alpha have been found in the milk of mothers who gave birth prematurely compared to mothers who delivered on time. EGF is important in the regeneration and repair of the intestinal epithelium, which could explain why breast milk has been shown to reduce the risk of necrotizing enterocolitis.^[35]EGF, TGF-alpha and human milk stimulate fetal cell proliferation in vitro in the small intestine, with the greatest increase in cell proliferation observed after exposure to human milk.

Certain bioactive substances and living cells in breast milk seem to influence the maturation and growth of the neonatal gut by transferring developmental information to the newborn. Although most of these biosubstances have been identified in amounts exceeding maternal serum levels, their exact role in human neonates is uncertain; Most current information comes from animal models whose development can differ significantly from that of a human baby.