Physiology, Breast Milk

Introduction

The production of breast milk initiates in larger amounts between 2 and 4 days after the birth of the baby and the breastmilk is said to have 'come in'. It is the sole best source of nutrition for an infant, providing an adequate amount of nutrients, growth factors, and antibodies required for the nourishment of the baby. Breast milk should be exclusively used for nutrition until 6 months of age after which breastmilk should be used in addition to complementary foods for at least 12 months of age. [1]

Issues of Concern

In many societies, formula feeding is becoming more prominent, and breast milk has become the least preferred choice.[2] Further evidence demonstrates how formula and bottle feeding lead to an increased risk of oral disease and alterations in oxygenation, thermoregulation, and the newborn's gut bacteria.[2]  

It is important to note that breast milk is not sufficient and nutritional supplementation is sometimes needed for low birth weight and preterm infants as elaborated below:

• VLBW infants require vitamin D supplements at a dose ranging from 400 IU to 1000 IU per day until 6 months of age.
• VLBW infants who are fed breast milk require daily calcium (120–140 mg/kg per day) and phosphorus (60–90 mg/kg per day) supplementation during the first month of life.
• VLBW infants who are fed breast milk require 2–4 mg/kg per day iron supplementation initiating at 2 weeks until 6 months of age.
• Infants born before 35 weeks gestation and are fed breast milk require iron supplementation of 0.2 mL/kg per dose 12-hourly starting at four weeks of life until six months of age.
• An infant born at less than 37 weeks requires Vitamine D supplementation(OsteVit-D) of 0.1 mL daily until 12 months of age.

The World Health Organization and the American Academy of Pediatrics recommend pasteurized human donor milk for preterm infants if the mother's breast milk has not 'come in'. In the case of anemia, the infant can have direct iron supplementation, or the mother's diet can be fortified with iron-rich foods.[3] As breast milk lacks Vitamins D and K, vitamin K is given at birth. It is recommended to expose the infants to the sun or supplement them with vitamin D. Maternal supplementation with 400–2000 IU of vitamin D per day increases the levels of vitamin D in breast milk, however, only a higher dose (2000 IU) achieves sufficient levels of 25-OH-D in the infant. 

Cellular Level

In the initial week after pregnancy, the mother secretes colostrum, a thick and yellow liquid. From days 7 to 14, the mother secretes transitional milk, a combination of colostrum and mature milk. After two weeks, the mature milk is formed and secreted.[4] The breast milk can be divided into the bluish-grey foremilk, present at the beginning of a feed which contains less fat, and the creamy white hindmilk secreted towards the end of a feed that is rich in fat.  Breast milk can differ depending on maternal health and diet, environmental exposure, gestational age, and the infant's age.[5] The breast milk generally consists of 87% water, 3 to 5% fats, 6.9 to 7.2% lactose, 0.8 to 0.9% proteins, vitamins, minerals, and bioactive substances.[6][4][5] It can yield up to 60 to 75 kcal per 100 ml. The colostrum (breast milk in the early days) has more proteins and immunoglobulins. Mature milk contains a higher percentage of carbohydrates.[6]

Fats

The fat content varies considerably with maternal diet and is also positively associated with weight gain during pregnancy.[6] Triglycerides account for the majority of the lipids. Saturated fatty acids account for nearly half of the fatty acids, with around 23% of palmitic acid. Breast milk contains two essential fatty acids: linoleic acid and alpha-linolenic acid. These get converted to arachidonic acid (AA) and eicosapentaenoic acid (EPA). EPA is further converted to docosahexaenoic acid (DHA).[5] 

Carbohydrates 

Breast milk mainly contains lactose. There are 30 or more oligosaccharides with the terminal Gal-(beta1,4)-Glc as well. They range from 3 to 14 saccharide units per molecule.[6] The stable concentration of lactose is important in maintaining a constant osmotic pressure in human milk.

Proteins

During early lactation, the protein content in human milk ranges from 1.4–1.6 g/100 mL, to 0.8–1.0 g/100 mL after three to four months of lactation, to 0.7–0.8 g/100 mL after six months.[7] Breast milk generally consists of casein and whey proteins. [8]The whey/casein ratio in human milk fluctuates between 70/30 and 80/20 in early lactation and decreases to 50/50 in late lactation. Whey consists of alpha-lactalbumin, lysozyme, lactoferrin, and immunoglobulin A.[5] Casein is more difficult to digest than is whey. Casein binds with calcium and phosphorus. Colostrum contains more whey than casein. Other proteins include folate-binding protein, Bifidus factor, lipase, amylase, PRP (Prolin Rich Peptide), alpha1-antitrypsin, antichymotrypsin, and haptocorrin.[5]

Glutamine is the amino acid present in the highest amount. It is approximately 20 times greater in mature milk than its lowest value in colostrum.

Vitamins and Minerals

Breast milk contains sodium, potassium, calcium, magnesium, phosphorus, and chlorine. The minerals iron and zinc are present in relatively low concentrations, but their bioavailability and absorption are high. Iron, copper, and zinc are also present in breast milk but vary in quantity. The infant's iron needs depend upon the mother's diet and health.[6]]  

Breast milk contains most vitamins except vitamin K and D. 

Bioactive Substances

Breast milk contains white blood cells, IgA, IgG, IgM, cytokines, chemokines, growth factors, hormones, and anti-microbial substances.[4] The epidermal growth factor is present abundantly and it stimulates maturation of the lining of the infant's intestine. The IgA antibody destroys bacteria and protects the mucosal surface of the gut.

Development

The breast development initiates at 6 weeks of development followed by the appearance of a linear elevation, called the 'milk line'. The milk line in the area of the breast gives rise to the mammary gland starting in the eighth week. The basal cells proliferate and invade the underlying mesoderm. Simultaneously, there will be the regression of a mammary segment, leading to the formation of a papillary primordium. Beyond the 31st week of gestation, the papillary bag becomes occluded, creating the Nipple-Areola Complex. The nipple appears at the time of birth.

The breast is made of glandular and adipose tissue anchored together with the framework created by Cooper's ligaments. The glandular tissue basically consists of alveoli and ducts. The lobes are made of lobules, which in turn are made of clusters of alveoli, which are small sacs lined by mammary secretory epithelial cells. Adipose tissue of the breast is located between lobes rather than within lobules. The alveoli end into minuscule ducts that join to form bigger ducts draining the lobules. The alveoli are surrounded by a basket of myoepithelial, or muscle cells, which contract and make the milk flow along the ducts. The breast milk is produced and stored in the alveoli and then pumped through the ducts during lactation. The ducts widen into lactiferous sinuses under the areola before narrowing at the base of the nipple and terminating at their orifices on the surface of the nipple. The areola also contains branched glands of Montgomery, which secrete an oily fluid that protects the skin of the nipple and areola during breastfeeding and produce a scent that attracts the baby to the breast.

During pregnancy, the mother undergoes stage II mammogenesis due to high progesterone; this increases secretory tissue in the breast. The high levels of chorionic gonadotropin form type three lobules in the breast alveoli. These lobules consist of epithelial cells and acini of increased size and number. During the latter part of pregnancy, the acini atrophy and give leeway for colostrum storage in the lumen.[9]

Organ Systems Involved

The organs and structures involved in breast milk formation are the mammary glands, the anterior pituitary gland, and the posterior pituitary gland. The individual roles of those organs are discussed below. 

Function

On the third day, the amount of breastmilk taken by the infant is about 300–400 ml/24 hours, and on the fifth day 500–800 ml. It averages at about 800 ml/day during the first 6 months. Infants who are breastfed according to their appetite are only able to empty out 70% of the available milk. The general composition of breast milk changes with time according to the need of the baby. When each nursing session begins, the foremilk satisfies the baby's thirst due to the high content. The hindmilk is more abundant in fat to provide the calories-dense nutrition a baby requires. Breast milk is required for postnatal intestinal function, immune ontogeny, and brain development.

There is extensive data supporting that breast milk is significantly superior to formula feeds and animal milk in preventing infections, such as Otitis media, lower respiratory tract infections, RSV bronchiolitis, sudden infant death syndrome, necrotizing enterocolitis, etc. It also reduces the propensity to develop obesity, allergy, asthma, wheezing, atopy, atopic dermatitis, eczema, celiac disease, Crohn’s disease, Diabetes mellitus type 1, Diabetes mellitus type 2, hypertension, hypercholesterolemia, acute lymphocytic leukemia, and acute myelogenous leukemia.

 The fat in breastmilk is necessary for growth regulation, inflammatory responses, immune function, vision, cognitive development, and motor systems in newborns.[5] DHA (docosahexaenoic acid) and Arachidonic Acid are required for cell differentiation and the development of active synapses in the nervous system. DHA and arachidonic acid are not present in other milk. 

The lactose in the milk aids in the absorption of minerals and calcium.[5] Furthermore, carbohydrates help certain strains of lactobacilli thrive in the gut, which helps control the intestinal flora.[6]

The concentration of protein in breast milk is lower than in animal milk. Higher protein content overloads the immature kidneys with waste nitrogen products. Compared to formulas, human breast milk contains higher whey protein levels, making digestion easier for the newborns. Infant formulas are high in casein whereas the cow’s milk contains only 18% whey out of total protein content. Furthermore, various whey proteins provide different functions necessary for the newborn. For example, immunoglobulin A antibody coats the gut surface and destroys bacteria. The lactoferrin and lysozymes help the immune system against pathogenic bacteria.[5] PRP stimulates the thymus to regulate the immune system in the body and stabilizes the hyperactive immune system due to autoimmune diseases and allergies in the body.  Alpha-lactalbumin is vital for the synthesis of lactose and binding of calcium and zinc ions. Bile-salt stimulated lipase present in breast milk assists in the complete digestion of fat in the small intestine [10] as opposed to the fat in artificial milk which is only partly digested. Glutamine is required to provide substrate (ketoglutaric acid) for the citric acid cycle, for its use as a neurotransmitter in the brain, and its role as a major energy substrate for intestinal cells.[11]

Vitamins and minerals play a critical role in the development of the newborn. They are necessary for enzymatic functions and constitute the building blocks of many molecular substances. However, vitamin D and K are not present in breast milk and require external supplementation. Iron is also essential to a newborn to prevent anemia.

Colostrum

It is the special yellowish milk only secreted in the first 2–3 days after the birth of the baby, in small amounts (about 30–60 ml/day). It is abundant in white blood cells and antibodies, especially IgA, to fight off the pathogens and contains about 20 specific antibodies against E.coli, Salmonella, Rotavirus, Candida, Streptococcus, Staphylococcus, Cryptosporidium, H.pylori, etc. It contains a higher proportion of protein, minerals, and fat-soluble vitamins (A, E, and K) than ordinary breast milk. Vitamin A is required to protect the eyes and form epithelium. It contains multiple growth factors. Insulin-like growth factors 1 and 2 are the most commonly found growth factors in colostrum. The epidermal growth factor is also present and it forms the intestinal lining needed to absorb the nutrients. It is vital for the neonate to be fed on colostrum and nothing else at this time. The composition of colostrum can be altered by maternal conditions such as eclampsia, diabetes, and anemia. 

Mechanism

A neonate may require breastfeeding every 1-3 hours for 10-20 minutes on average. However, the frequency and duration of breastfeeding sessions decreases as the child gets older, as he can recieve more amount in less time. Two hormones are involved in the development of breast milk: prolactin and oxytocin.

Prolactin stimulates milk production. It increases during pregnancy to prepare the mammary tissue to start forming the milk by stimulating epithelial proliferation. However, due to high levels of progesterone and estrogen, prolactin is inhibited from forming any milk. After placental delivery, progesterone and estrogen levels fall, allowing prolactin to exert its effect and secrete the milk. [12][13] Oxytocin acts to contract the myoepithelial cells to eject the stored milk.[9][3] The baby suckling on the nipple also stimulates prolactin secretion. It reaches its peak levels in the blood about half an hour after the feeding. And stimulates the production of milk for the next feed which collects in the lumen of the alveoli and ducts. Prolactin secretion is maximal at night time. Thus, breastfeeding at night is highly recommended.[12] 

Oxytocin is known as the "let-down" hormone. It helps to contract myoepithelial cells present around the alveoli, causing ejection of the breast's already-made milk.[12][13] The ducts beneath the areola fill with milk and become wider during a feed when the oxytocin reflex is active. Oxytocin is produced more quickly than prolactin. Oxytocin secretion occurs when the mother expects a feed or starts seeing, hearing, smelling, or even thinking about the baby. Infant sucking on the nipple also stimulates oxytocin secretion. This reflex explains why a mother and child should be roomed together as often as possible. If the mother is emotionally unbalanced, this reflex can be affected. Oxytocin also promotes bonding and affection between the mother and child

Initially, the amount of prolactin produced is positively related to the stimulation of the nipple. However, a few weeks later, the prolactin levels and quantity of milk produced are not tightly associated. But milk secretion stops if the mother stops breastfeeding. When breastfeeding is stopped, the Feedback Inhibitor of Lactation (FIL) collects and stops the cells from secreting more milk. When breast milk is removed during feeding or by the expression, FIL is also removed resuming the production of milk. Hence, FIL makes sure an adequate amount of milk is produced and prevents the breast from becoming too full.

Prolactin is beneficial to the mother as well. It causes a feeling of happiness and relaxation. Prolactin secretion also affects the release of gonadotropin-releasing hormone (GnRH). Inhibition of GnRH decreases the release of follicle-stimulating hormone and luteinizing hormone, which leads to a natural birth control mechanisms in the mother called lactational amenorrhea.[12]

Pathophysiology

One of the main maternal concerns is not having enough breastmilk. Since breast milk is indispensable to a newborn, physicians should be able to investigate milk supply difficulties. Signs include low weight gain, dry mucous membranes of the baby, weak cry, infrequent hard stools, and decreased urine output.[14] Many factors can affect breast milk supply, such as poor maternal health (e.g., anemia), abnormalities in the breast tissue, retained fetal products in-utero, urinary tract infections in the mother, and poor feeding habits.[14] Effective feeding habits and optimizing the mother's health status helps to achieve optimum feeding.[14]

Breastfeeding Jaundice: It usually occurs in the first week of life, due to the infant not receiving sufficient milk. This causes increased enterohepatic circulation and decreased elimination of bilirubin from the body resulting in jaundice. It is commonly caused by difficulty breastfeeding, improper latching, or other reasons that might interfere with breastfeeding. Signs of dehydration are normally present. Treatment includes continued breastfeeding, increased frequency of feeds, and counseling by a lactation consultant. Spontaneous resolution usually occurs in the third week of life. 

Breastmilk Jaundice: It starts on 3-5 days after birth, peaking at 2 weeks of age. lasting several weeks after birth. High levels of beta-glucuronidase in breast milk deconjugate intestinal bilirubin and increased enterohepatic circulation. Weight gain is adequate and examination is usually unremarkable. Spontaneous resolution usually occurs by 12 weeks of life and treatment is generally not required.

Milk/Soy Induced Colitis: It is a hypersensitive gastrointestinal disorder to allergens present in breast milk, which presents at 2-8 weeks of age with regurgitation or vomiting, painless bloody stools. Eczema may be present as well. It is not IgE-mediated with concomitant soy milk reaction in 30% of infants. Risk factors for this condition include a family history of allergy, eczema or asthma. Treatement involves the elimination of milk and soy from maternal diet. Spontaneous resolution occurs by 1 year. 

Clinical Significance

Breastfeeding correlates with decreased risk for cardiovascular diseases, atopic diseases, and several infectious diseases. Additionally, breastfeeding is associated with a reduction in the risk of behavioral and developmental disorders.[2] Breast milk is vital for the newborn's development. However, due to the increased norm of working mothers, breast milk pumping and storage has become a widespread practice. The maintenance of this practice is crucial to prevent the spread of pathogens through expressed milk. Preserving the integrity of the breast milk is essential, hence using proper hygiene is advised. Furthermore, short-term storage of the milk can be achieved by the refrigerator to prevent contamination.[15]

The breast milk is contraindicated in the following conditions:

• If the mother is on chemotherapy or recent/current use of radioactive agents
• If the mother has Human T-cell lymphotropic viral infection or untreated brucellosis
• If the mother has untreated/sputum positive tuberculosis
• If the mother drinks alcohol or abuses drugs
• If the mother has suspected or untreated HIV
• If the infant is diagnosed with galactosemia

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Disclosure: Rutvi Shah declares no relevant financial relationships with ineligible companies.

Disclosure: Sarah Sabir declares no relevant financial relationships with ineligible companies.

Disclosure: Ali Alhawaj declares no relevant financial relationships with ineligible companies.