The circadian variation of amino acids and melatonin in human milk and their potential sleep-wake regulation.

After completing this article, readers should be able to: Over the past 50 to 60 years, human milk has been described and recognized as the best first food for human infants; breast is best! Human milk provides substantial nutritional, cognitive, emotional, and immunologic benefits for the infant. Such ongoing acclamation is based on the observations and experiences of mothers, families, midwives, doulas, nutritionists, nurses, physicians, and scientists.Over the past 30 years, scientific study and research have accumulated and now constitute a large body of evidence documenting the actual benefits of breastfeeding for the infant and the mother. This article examines and references much of this evidence-based data in describing human milk and how it contributes to the health and well-being of infants and mothers.The Agency for Healthcare Research and Quality (AHRQ) Report on Breastfeeding in Developed Countries summarizes evidence (published in English through May 2006) on breastfeeding in maternal and infant health. (1) More than 9,000 abstracts were considered, and data from more than 400 individual studies were included after evidence-based review of meta-analyses, updated systematic review of the data, and newly performed systematic reviews. It is important to emphasize that this report included data from developed countries only. Table 1presents definitions of breastfeeding that are particularly useful in "quantification" as standard definitions used in clinical studies.Nineteen specific outcomes were reviewed by the AHRQ research team, including 13 for term infants and six for mothers. The outcomes for infants were: incidence of acute otitis media, atopic dermatitis, gastrointestinal (GI) infections, lower respiratory tract infections, asthma, obesity, type 1 and 2 diabetes, childhood leukemia, infant mortality, and sudden infant death syndrome as well as cognitive development and the risk of cardiovascular disease. Factors studied in mothers were: return to prepregnancy weight and incidence of type 2 diabetes, osteoporosis, postpartum depression, breast cancer, and ovarian cancer.For infants, the meta-analyses or systematic reviews strongly favored breastfeeding over not breastfeeding for a reduced risk of acute otitis media, GI infections, asthma (regardless of whether there was a family history of asthma), type 2 diabetes, leukemia, and sudden infant death syndrome. The meta-analysis of GI infections reported a crude odds ratio for 14 cohort studies of 0.36 (95% confidence interval [CI] 0.32 to 0.41) strongly favoring breastfeeding (ever) in reducing the risk of GI infection in infants younger than 1 year of age (Fig. 1). Another analysis reported on two case-control studies demonstrating a summary odds ratio of 0.54 (95% CI 0.36 to 0.80) again favoring breastfeeding. A separate analysis demonstrated that infants breastfeeding exclusively for greater than 3 months' or greater than 6 months' duration had significant reductions in the risk of acute otitis media compared with infants who were never breastfed. The analysis of infants developing atopic dermatitis (who had a family history of atopic disease) demonstrated that the risk for atopic dermatitis was lower in infants breastfed exclusively for longer than 3 months compared with children who were breastfed for less than 3 months. An analysis examining lower respiratory tract infections showed an overall reduced risk of hospitalization due to lower respiratory tract infections in infants (<1 year of age) who were breastfed exclusively for 4 months or longer compared with infants who were never breastfed (Fig. 1).The report presented two meta-analyses and a systematic review demonstrating a reduced risk of breast cancer associated with breastfeeding primarily in premenopausal women. One meta-analysis that included 45 studies showed a 4.3% reduction in risk for each year of breastfeeding. A second meta-analysis that included 23 studies demonstrated a 28% reduced risk of breast cancer for 12 months or more of breastfeeding. The AHRQ team performed a meta-analysis of 9 "fair" quality studies that included 4,387 cases of ovarian cancer and more than 10,000 controls. This new meta-analysis showed an association between breastfeeding and a reduced risk of ovarian cancer. Cumulative lifetime breastfeeding duration of more than 12 months was associated significantly with a decreased risk of ovarian cancer compared with never breastfeeding. This benefit was not seen for cumulative duration of breastfeeding of less than 12 months (Fig. 2). Additional data are needed to confirm a dose-response relationship between breastfeeding and a reduced risk of ovarian cancer.The analysis for type 2 diabetes, involving two very large cohort studies, showed that breastfeeding was associated with a reduced risk of developing type 2 diabetes in women who did not have a history of gestational diabetes. Each additional year of lifelong breastfeeding was associated with a 4% to 12% risk reduction in the two different cohorts. Breastfeeding did not appear to lead to a reduced risk of developing type 2 diabetes in women who had gestational diabetes. The studies on return to prepregnancy weight, osteoporosis, and postpartum depression were unable to demonstrate an association between breastfeeding and these specific maternal health outcomes due to methodologic issues and the effect of other contributing factors or confounders.These high-quality, evidence-based data from the AHRQ Report support breastfeeding as providing significant health benefits to both the mother and infant, even in developed countries. A larger body of evidence from developing countries examines the benefits of breastfeeding in locales where the risk of infection in infants and children is high due to poor sanitation, low water quality, contaminated food sources, and other variables. This benefit is well documented for diarrheal disease, respiratory infections, and otitis media.Beyond the evidence-based medicine measures is the realm of attachment and bonding between infant and mother and the psychological and developmental benefits of breastfeeding for the mother and infant. How these spheres are influenced by breastfeeding has been studied extensively in many different countries and cultures. Close and frequent contact between the mother and infant, especially skin-to-skin contact, affects the mother's attachment to the infant positively. The positive feelings affected by the close (skin-to-skin) and frequent early contact facilitate successful breastfeeding, longer duration of breastfeeding, and more attachment behavior (fondling, kissing, and caressing the infant). Recognition of these effects has led to more direct contact between the infant and his or her parents in the delivery and postpartum areas. Such recognition has supported the recommendation to allow placement of the infant in direct skin-to-skin contact with the mother in the first hour after birth to encourage successful breastfeeding. The multiple contributory factors to infant development makes it difficult to demonstrate a causative connection between early skin-to-skin contact or breastfeeding and overall infant and child development, emotional stability, personality, attachment, or person-to-person interactions.The impact of different methods of feeding infants on the onset of allergy has been researched. A meta-analysis of 18 prospective studies involving term infants who had a family history of atopy found a reduction of 42% (95% CI, 8% to 59%) in the risk of atopic dermatitis for infants breastfed for at least 3 months compared with those who were breastfed for less than 3 months. (1)Studies on asthma were less definitive. The AHRQ reported that breastfeeding for at least 3 months was calculated to provide a 27% (95% CI, 8% to 41%) reduction in the risk of asthma in children who had no family history of asthma compared with children who were not breastfed. Children who had a family history of asthma had a 40% risk (95% CI, 18% to 57%) reduction in the occurrence of asthma before 10 years of age if breastfed for 3 months compared with those not breastfed. The risk for children older than 10 years is less clear. Exclusive breastfeeding for the first 6 months is recommended by the American Academy of Pediatrics (AAP) for many reasons, including reducing the risk of allergy. Further if supplementation is necessary, an amino acid-based formula is recommended (hypoallergenic formula).The milk available in the breast after 16 weeks' gestation is called prepartum milk. When the infant delivers and is placed at the breast (or is allowed to find his or her way) to suckle, the milk is colostrum for the next few days. A gradual change from this transition milk to mature milk usually occurs by 14 days. Postpartum colostrum is called "the first immunization" because it contains high concentrations of antibodies and other infection-protective elements, including cells. Colostrum is high in total protein, low in carbohydrate, and lower in fat than mature milk. The amount of milk produced in the first 24 hours after birth is approximately 50 g, with 190 g produced by the second 24 hours, 400 g by the third 24 hours, and 1,100 g/24 hours by the fourteenth day (800 to 1,000 mL). Human milk and cow milk differ substantially in their composition (Table 2).The proteins differ in quality and quantity. In its unaltered form, cow milk contains too much protein, too much casein, too much sodium, and too much phosphorus and has too high a solute load for a human infant. Formulas have been designed to improve these issues. Cow milk does not contain any taurine, an amino acid that has high concentrations in human milk and is essential to infant brain growth. The profile of amino acids in cow milk differs significantly from human milk, especially phenylalanine and tyrosine, which are at high concentrations in cow milk and formula and contribute to problems in phenylketonuria.The effect of higher protein in infant formula recently has been questioned by investigators of the obesity epidemic. It has been suggested that a constant intake of high protein in infancy stimulates the metabolic rate and contributes to the long-term obesity of formula-fed infants. After processing, cow milk and infant formulas contain no cells, no enzymes, and no antibodies or other active protective agents and do not support the maintenance of physiologic flora of the infant's GI tract.Docosahexaenoic acid (DHA) has received considerable attention because studies in preterm infants have demonstrated improved visual acuity and auditory acuity in those fed human milk compared with those fed regular preterm formula. When DHA was added to formula, the acuity improved but did not reach the scores achieved by breastfed infants. DHA and omega-3 fatty acids derived from bacterial culture are added to many formulas, although a benefit has not been proven.Vitamin concentrations in human and cow milk are comparable, except for vitamin C, which is significantly higher in human milk (100 mg/d). Vitamins in infant formula exceed the concentrations found naturally. Vitamin D has become an important issue because the vitamin D generated in human skin from exposure to sunshine has diminished through the use of sunscreen, wearing of clothing to shade from the sun, pollution of the air by industrial waste, and migration of dark-skinned populations to climates with less sun. Pregnant women have been documented in recent decades to pass less vitamin D to the fetus, so newborns lack sufficient stores at birth. As a result, breastfed infants now are given 400 U daily from birth. Investigative work continues on the benefits of providing pregnant and lactating women with 1,000 U of vitamin D daily. Most, but not all, infant formulas contain 400 U of vitamin D in 26 to 32 oz of reconstituted formula.Vitamin K content presents an important issue for the newborn who is born with low concentrations, even when the mother receives extra doses at the time of delivery. Hemorrhagic disease of the newborn, with GI or intracranial hemorrhage and generalized bleeding, can present early or up to several weeks after birth and is due to relative deficiencies of vitamin K-dependent coagulation factors. Such deficiency has resulted in all newborns receiving 1 mg of vitamin K intramuscularly at birth, regardless of the proposed mode of feeding. If vitamin K is administered orally, multiple doses should be provided. Formula has extra vitamin K, so an infant who receives 26 to 32 oz per day of formula receives 4 mg of vitamin K orally daily. Concentrations in human milk and cow milk are lower.Neonates and infants are immunologically immature and at increased risk for infection. Such developmental immune defects are only some of the factors that place infants at greater risk of infection. In the first 6 postnatal months, phagocyte function is immature, with limited ability to migrate to the site of infection, and reserve production of phagocytes in response to infection is limited. Cell-mediated immunity develops throughout childhood. Defects are particularly apparent in the first 6 months after birth, including decreased cytokine production, decreased natural killer cell function, poor stimulation of B cells for antibody production, and limited numbers of mature functioning T cells. In addition, function of the classical and alternative pathways of complement formation and activation is decreased. Immunoglobulin (Ig) production is limited in amount and repertoire, including poor isotype switching, limited IgG subclass production, and low serum IgA concentrations through 7 to 8 years of age.Human milk not only bolsters the infant's immature immune response by providing numerous bioactive factors that dynamically affect the innate, adaptive, and mucosal immunity against specific infectious agents but also by influencing immune system development and maturation of the mucosal barrier. A very clear dose-response relationship has been documented between the amount (full [exclusive], partial, token) and duration of breastfeeding and the benefits gained by the infant and mother. (See Table 1 for the definitions.) Most bioactive factors exert their effects at the level of the mucosal immune system. Igs are the best recognized and studied bioactive components in human milk. Igs in human milk are predominantly secretory IgA, with much smaller amounts of IgM and IgG. Colostrum contains higher amounts of Igs and immunologically competent mononuclear cells than transitional or mature milk. The Igs function by binding directly to specific microbial antigens, blocking binding and adhesion to host cells, enhancing phagocytosis, and modulating local immune response. Table 3 in the online edition of this article lists specific antibodies that have been identified in human milk.The actual antibodies against specific microbial agents present in an individual woman's milk depends on her exposure and response to the particular agents. Not every mother has antibodies in her milk against every microbe. The predominant action of Igs in human milk is seen at the mucosal level of the infant's mouth, nasopharynx, and GI tract, where they bind to and block the infectious entry of microbial agents through the mucosal barrier. Although best recognized and remembered in association with "specific" protection against individual infectious agents, Igs provide only a small portion of the overall immunologic benefit of human milk.Other important individual bioactive proteins include lactoferrin, lysozyme, alpha-lactalbumin, and casein. Lactoferrin exerts its effects via iron chelation, which contributes to limiting bacterial growth, blocking adsorption and penetration of viruses and adhesion of bacteria, and enhancing intestinal cell growth and repair. Lysozyme binds to endotoxin, increases macrophage activation, and contributes to bacterial cell wall lysis. Lactalbumin transports calcium and enhances the growth of Bifidobacterium, and a modified lactalbumin (in the gut) affects immune modulation. Casein limits adhesion of bacteria and facilitates the growth of Bifidobacterium. Carbohydrates are an important nutritional component in human milk, and the specific carbohydrates lactose, oligosaccharides, and glycoconjugates act as bioactive factors. Oligosaccharides act as prebiotics, enhancing the growth of specific probiotic bacteria in breastfed infants, and both oligosaccharides and glycoconjugates bind specific microbial antigens.Lipids in the form of triglycerides, long-chain polyunsaturated fatty acids, and free fatty acids (FFAs) have a lytic effect on many viruses and are active against Giardia as well. Nucleotides, nucleosides, and nucleic acids comprise more than 15% of the nonprotein nitrogen in human milk. Nucleotides serve many crucial roles in energy metabolism, nucleic acid production, and signal transduction, processes of increased importance during the cellular activation and replication related to an active immune response. Research related to the "essential" nature of nucleotides in protection against infection has led to the addition of nucleotides to some infant formulas. Cytokines and soluble receptors of cytokines are other examples of bioactive factors that serve several functions. Cytokines can act as functional growth factors and have both inflammatory and anti-inflammatory effects in different situations.Hormones and growth factors, including erythropoietin, epidermal growth factor, insulin, insulin-like growth factor, nerve growth factor, and transforming growth factor-alpha, stimulate the growth and maturation of the GI tract and, to a degree, systemic growth. These bioactive factors are less specific than Igs, but by acting in concert with multiple factors, they provide the major portion of protective effects from human milk.The concept of immune protection without an extensive and potentially damaging inflammatory response is gaining in significance in general medicine and in breastfeeding medicine. Many of the same protective bioactive factors act at the mucosal level without stimulating a significant inflammatory response, which indirectly decreases inflammation and possible local tissue damage. Certain factors limit further inflammatory stimulation: lactoferrin blocks activation of complement, and lysozyme inhibits neutrophil chemotaxis and limits formation of toxic oxygen radicals. Various enzymes in human milk break down inflammatory molecules: catalase destroys hydrogen peroxide, histaminase destroys histamine, and arylsulfatase degrades leukotrienes. Various soluble receptors in human milk (IL-1Ra, STNF-alpha R1 and R2) bind to specific cytokines, blocking their inflammatory action.Vitamins A, C, and E, which are present in higher concentrations in human milk than in cow milk, scavenge oxygen radicals. Catalase and glutathione peroxidase as well as lactoferrin serve multiple purposes and have antioxidant properties. Prostaglandins in human milk limit superoxide production. The sum total of these anti-inflammatory effects of human milk occurring at the mucosal level limits damage to the mucosal barrier and facilitates its ongoing growth and development to further enhance human milk's protection of the infant.The concept that "normal" intestinal microflora influence the development of the local mucosal immunity and even "prime" systemic immunity is being supported by new research. Pathogen-associated molecular patterns in the microflora are recognized by toll-like receptors and may contribute to the expression of toll-like receptors on intestinal epithelial cells as well as lead to "programming" of systemic T-helper cell type 1 (TH1), TH2, and TH3-like T-cell responses. Probiotic bacteria are organisms that live in the additional benefits on the which include with between cells, production of increased production, increased production of specific fatty and development of the mucosal immune usually are oligosaccharides after lower the of the local and the amount of available enhance the growth of probiotic bacteria in the Oligosaccharides are the third component in human milk in of quantity. Cow milk and formula contain less than of the oligosaccharides in human milk by The microflora of breastfed infants include and Bifidobacterium, which comprise up to of the The small portion of bacteria include and as well as and other organisms in even smaller The microflora of formula-fed infants are primarily of organisms and in much larger numbers than in breastfed infants and include very small amounts of and Bifidobacterium. and oligosaccharides, acids, including which lower the in the and limit the growth of as and molecular that by of are the of GI microflora and factors influencing intestinal and immunologic development at the level of the studies have suggested a protective of specific intestinal microflora against the risk of developing in preterm and very all the evidence for the immunologic benefits of human milk and the protection infants against specific organisms and separate clinical data also the of specific infections through human milk or direct contact with an maternal Although only a few infections are through human milk human viruses 1 and 2 and and these viruses are important because of their for or in the infant. In addition, other infections that are by human milk or breast contact should be in specific of infection through human milk is compared with the more of for and infants. infection is occurring the infection is due to through the birth and postnatal infection occurs via or contact other than with the The predominant of and the of infection are important in different clinical of the for via human milk for organisms can be and 4 and in the online edition of this article for of the for bacteria and infection of the mother with or is a to breastfeeding. on have documented approximately a rate in breastfed infants, rate in infants, and rate in exclusively formula-fed infants. that 1 of human milk can contain 1,000 T cells with studies from of that have high of have reported significant reductions in of the from mother to infant with of breastfeeding or limiting breastfeeding to less than 6 months' infection in the mother is infection that can be via human milk to the infant. In the and other of the where is successful and to breastfeeding are and mothers who have infection have been not to their infants. In of the where there is an increased risk of infectious nutritional and significant and for infants who are not breastfed and feeding is not breastfeeding by an mother can the infant the best of is in human milk and can be as and Factors associated with an increased risk of via breastfeeding include feeding breastfeeding, duration of breastfeeding, maternal and high lower in the and or in the mother. studies have documented that of the mother with breastfeeding can lead to lower for infants and lower for both mothers and infants. of the infant with breastfeeding also has been associated with decreased to the infant. Additional research on breastfeeding, and the infant's and growth are needed before an can be infection or even recent infection in a breastfeeding mother is not a to breastfeeding. infection via human milk occurs but is if significant in the term infant. In breastfeeding has been described as immunization" in the term infant. and very infants are at risk for significant postnatal infection via breastfeeding. This postnatal infection is more to between 3 and 12 weeks when occurs and milk can the load in human milk. A has been for infants human milk in that include preterm and very infants. The mothers for before providing human milk to their infants, or human milk from mothers before its and infants in the for evidence of acute the protective effects of a is the only other for which there has been evidence for via human milk with any studies the of as well as IgM and IgG antibodies against in human milk, but no clear evidence significant in infants through breastfeeding by mothers who have infection. The viruses as or is through contact with skin that contain the on the mother's or not through in the milk. of breastfeeding and milk from the mother's breast that has an identified due to of these viruses may be for the infant with maternal usually is to allow breastfeeding to via the respiratory respiratory acute respiratory are not through human milk. Most by the time a specific respiratory is in the the infant has been via respiratory is no to breastfeeding or the use of human milk, except when disease in the mother the ability to human milk. The numerous bioactive factors Igs if it is early in the maternal in human milk can provide the infant some ongoing bacterial infections in the mother is infection of the or breast or breast that the bacteria the milk or directly the infant's (See Table 4 for bacterial infections in the The risk of in the mother is related to via respiratory which is the same for breastfeeding or formula-fed infants in contact with their mothers. or of the breast are Breastfeeding or use of human milk from the mother who has can the mother is receiving and the infant is receiving or A infection of the breast can with breastfeeding. Breastfeeding or use of human milk can when the mother is with the after a during the mother's 24 hours of for the infant in with the maternal additional the same used to a specific infection in the mother are used and are in the infant and in the mother's milk. do human milk, but usually in very low

When it comes to feeding the newborn, human milk is, from an evolutionary perspective, the biological norm, the time-tested standard of care. The health benefits to the infant of breast-feeding have been amply documented; numerous studies strongly indicate significantly decreased risks of infection, allergy, asthma, arthritis, diabetes, obesity, cardiovascular disease, and various cancers in both childhood and adulthood. Among the more fundamental disadvantages of not being breastfed is a loss of immunologic protection afforded by maternal colostrum, a “pre-milk” fluid secreted only during the first days after delivery, as well as numerous other bioactive factors that help protect the infant through the first two years of life, when the immune and nervous systems are incompletely developed. Nevertheless, given the tendency for persistent organic pollutants (POPs), pesticides, heavy metals, and other contaminants to accumulate in human milk, researchers and parents alike are asking whether the nursling’s exposure to these pollutants might reduce or even override the health benefits.

Free secretory component (free SC) in human milk is a critical constituent of secretory IgA (SIgA) for immune exclusion, but its concentration in human milk is unknown. To evaluate the relationship between free SC and SIgA, the influence of maternal factors (vaccination during pregnancy, allergy, previous infections, nutrition, mode of delivery and active lifestyle) on the concentrations of those secretory immune components in human milk was investigated. Concentration of active free SC and SIgA in 124 milk samples from 91 mothers were measured via ELISA. Free SC in milk from Tdap-vaccinated mothers was lower than the Tdap-flu-vaccinated, flu-vaccinated or Rhogam-vaccinated mothers. Free SC in mothers who had a cesarean delivery was higher than mothers who had a vaginal delivery. Free SC in the nonallergic group was higher than the allergic group. Free SC was higher in mothers who rarely/never eat junk food, than in mothers who always/frequently eat junk food. Free SC also was higher in the moderate exercise group (active lifestyle) compared with the group who rarely/never exercise (sedentary lifestyle). Free SC in human milk was not affected by previous maternal infection or probiotic supplementation whereas SIgA was not changed by all investigated maternal factors. This study suggests that active free SC is more impacted by maternal factors than active SIgA in human milk. Active free secretory component (free SC) is more impacted by maternal factors than active secretory IgA (SIgA) in human milk. Vaccination during pregnancy, allergy, nutrition, type of delivery and active lifestyle affect the secretion of free SC in human milk, but not SIgA secretion. Free SC in human milk is a critical constituent of secretory IgA (SIgA) for immune exclusion against pathogens and its active concentration in milk strongly varies between mothers, partially due to their specific maternal background.

We present a case of a 27-year-old woman in whom idiopathic hypersomnolence was diagnosed in adolescence with adequate symptomatic control on daily dosage of 250 mg of modafinil. She maintained this dosage throughout her pregnancy and during the peripartum period, but did not breastfeed her newborn because of a lack of information on the transmission of modafinil in human breast milk. Samples of her breast milk were obtained at various times over a 24-hour period and analyzed using liquid chromatography mass spectrometry. The relative infant dose was calculated to be 5.3%, below the threshold of concern for drug passage via breast milk. This is the first reported case of modafinil transfer into human breast milk. Given the drug's use in a variety of sleep disorders, the results of this case can be used to advise breastfeeding mothers prescribed modafinil.

Oligosaccharides in Human Milk and Bacterial Colonization

A new method for purifying N-Glycans released from milk glycoprotein

Longitudinal changes in choline concentration and associated factors in human breast milk

BackgroundHuman milk dynamically adapts its composition of immunoglobulins (Igs), cytokines, and other proteins as lactation progresses, influencing the infant’s immune development and protection. Understanding how maternal factors, such as parity, influence the composition of human milk can provide strategies aimed at enhancing infant immune protection and reducing early-life infections. This study aims to investigate whether the immune composition of human milk differs based on parity, and if so, how these changes are related to infections in early life.MethodsThe study included 75 healthy mother-infant pairs from the MAMI cohort (Clinical Trial Registry NCT03552939), with milk samples collected from the same mothers at days 7 and 15 postpartum, during transitional lactation stage. Igs, cytokines, and adipokines were quantified using multiplex immunoassays and ELISA. A comparison was conducted between primiparous and multiparous mothers regarding both the overall and individual composition of immune components in human milk at each time point, as well as their evolution throughout the transitional phase.ResultsInfants from multiparous mothers recorded higher infection rates in early life than those of primiparous mothers. Some human milk immune components also differed by parity, with multiparous mothers exhibiting higher levels of IgA, total IgG, IgG1, IgG2, IgG3, IgE, and IL-23 at the beginning of the transitional phase (day 7), as well as higher IL-18 and IL-21 levels toward its end (day 15), compared to primiparous mothers. Additionally, the evolutionary pattern in levels of Igs, cytokines, and adipokines throughout the transitional milk stage also differed. Moreover, in multiparous mothers, higher levels of IgG, particularly IgG1 and IgG2 (day 7), as well as IL-18 and IL-22 (day 15), were associated with reduced infant infections, highlighting their potential protective role.ConclusionsParity is a maternal factor that influences some immune components of human milk during the transitional stage and may be linked to the susceptibility of infants to infections during the first 6 months of life. Future studies aimed at analyzing the impact of the parity factor, among others, on the progression of immune components in human milk may contribute to a better understanding and improved strategies for newborn health.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13006-025-00770-0.

BackgroundMany studies support the protective effect of breastfeeding on respiratory tract infections. Although infant formulas have been developed to provide adequate nutritional solutions, many components in human milk contributing to the protection of newborns and aiding immune development still need to be identified. In this paper we present the methodology of the “Protecting against Respiratory tract lnfections through human Milk Analysis” (PRIMA) cohort, which is an observational, prospective and multi-centre birth cohort aiming to identify novel functions of components in human milk that are protective against respiratory tract infections and allergic diseases early in life.MethodsFor the PRIMA human milk cohort we aim to recruit 1000 mother–child pairs in the first month postpartum. At one week, one, three, and six months after birth, fresh human milk samples will be collected and processed. In order to identify protective components, the level of pathogen specific antibodies, T cell composition, Human milk oligosaccharides, as well as extracellular vesicles (EVs) will be analysed, in the milk samples in relation to clinical data which are collected using two-weekly parental questionnaires. The primary outcome of this study is the number of parent-reported medically attended respiratory infections. Secondary outcomes that will be measured are physician diagnosed (respiratory) infections and allergies during the first year of life.DiscussionThe PRIMA human milk cohort will be a large prospective healthy birth cohort in which we will use an integrated, multidisciplinary approach to identify the longitudinal effect human milk components that play a role in preventing (respiratory) infections and allergies during the first year of life. Ultimately, we believe that this study will provide novel insights into immunomodulatory components in human milk. This may allow for optimizing formula feeding for all non-breastfed infants.

BackgroundDespite global public health organizations endorsing breastfeeding or human milk (HM) as the optimal source of nutrition for infants, detailed knowledge of how HM composition influences infant growth is lacking. In this commentary we summarize and interpret the key findings of a large systematic review on HM components and child growth (N = 141 articles included). We highlight the most consistent associations, discuss study quality issues, explore socio-economic and time trends in this body of research, and identify gaps and future research directions.Key Findings of Systematic ReviewWe grouped HM components into three categories: micronutrients (28 articles), macronutrients (57 articles), and bioactives (75 articles). Overall, we struggled to find consistent associations between HM components and infant growth. The majority of studies (85%) were of moderate or low-quality, with inconsistent HM collection and analysis strategies being identified as the most substantial quality concerns. Additional quality issues included failing to account for potential confounding by factors such as breastfeeding exclusivity and maternal body mass index.Considerations for Future Human Milk ResearchMany opportunities exist for the future of HM research. Using untargeted metabolomics will expand our understanding of HM components beyond previously defined and well-understood components. Machine learning will allow researchers to investigate HM as an integrated system, rather than a collection of individual components. Future research on HM composition should incorporate evidence-based HM sampling strategies to encompass circadian variation as well as infant consumption. Additionally, researchers need to focus on developing high quality growth data using consistent growth metrics and definitions. Building multidisciplinary research teams will help to ensure that outcomes are meaningful and clinically relevant.ConclusionDespite a large body of literature, there is limited quality evidence on the relationship between HM composition and infant growth. Future research should engage in more accurate collection of breastfeeding data, use standardized HM collection strategies and employ assays that are validated for HM. By systematically evaluating the existing literature and identifying gaps in existing research methods and practice, we hope to inspire standardized methods and reporting guidelines to support robust strategies for examining relationships between HM composition and child growth.

Human Milk Components and the Infant Gut Microbiome at 6 Months: Understanding the Interconnected Relationship

Nutritional exposure and, therefore, the metabolic environment during early human development can affect health later in life. This can go beyond the nutrients consumed; there is evidence that the development and modulation of the gut microbiome during early life can affect human growth, development, and health, and the gut microbiome is associated with the risk of obesity later in life. The primary aim of this review was to evaluate existing evidence, to identify the components of human breast milk, which may modulate the gut microbiome, and to assess the impact of the gut microbiome on the risk of becoming obese later in life. This review also considers maternal and child characteristics, and confounders of breastfeeding and how they impact on the infant gut microbiome. Current evidence supports a positive association between fecal, branched short-chain fatty acids and human milk oligosaccharide diversity and a gut microbiome associated with better metabolic health. A negative correlation was found between microbiome diversity and human milk oligosaccharide evenness, which was associated with a greater fat mass and percentage of fat. The components of human breast milk, including oligosaccharides, probiotics, milk fat globule membrane, and adiponectin, were hypothesized to positively influence infant growth and body weight by modulating the microbial diversity and composition of the gut. Maternal diet, timing and duration of breast feeding, and the mode of delivery were all shown to affect the human milk microbiota. However, more experimental studies with long follow-up are required to shed light on the governing mechanisms linking breast milk components with a diverse infant microbiome and healthier body weight later in life.

Breast-feeding is currently recommended to prevent the development of allergic diseases; however, data are conflicting and mechanisms are unclear. The immunomodulatory composition of human milk is poorly characterized and varies between mothers. We and others have shown that high levels of human milk IgA and certain cytokines and human milk oligosaccharides are associated with protection against food allergy in the infant, but it is unclear whether they are responsible for or simply biomarkers of the vertical transfer of protection. Because human milk has pre- and probiotic properties, the anti-allergy protection afforded by human milk may be due to its control on the developing gut microbiome. In mice, murine milk IgA supports gut homeostasis and shapes the microbiota, which in turn diversifies the intestinal IgA repertoire that reciprocally promotes the diversity of gut microbiome; these mechanisms are poorly understood in humans. In addition, several human milk bioactives are immunostimulatory, which may in part provide protection against allergic diseases. The regulation of immunologically active components in human milk is incompletely understood, although accumulating evidence suggests that IgA and cytokines in human milk reflect maternal exposures. This review summarizes the current literature on human milk components that have been associated with protection against food allergy and related allergic disorders in early childhood and discusses the work relating to regulation of these levels in human milk and possible mechanisms of action.

Role of human milk components in gastrointestinal development: Current knowledge and future NEEDS

Human milk (HM) provides a plethora of nutritional and non-nutritional compounds that support infant development. For many compounds, concentrations vary substantially among mothers and across lactation, and their impact on infant growth is poorly understood. We systematically searched MEDLINE, Embase, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. Outcomes included weight-for-length, length-for-age, weight-for-age, body mass index (in kg/m2)–for–age, and growth velocity. From 9992 abstracts screened, 144 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Micronutrients (vitamins and minerals) are reported here, based on 28 articles involving 2526 mother-infant dyads. Studies varied markedly in their designs, sampling times, geographic and socioeconomic settings, reporting practices, and the HM analytes and infant anthropometrics measured. Meta-analysis was not possible because data were sparse for most micronutrients. The most-studied minerals were zinc (15 articles, 1423 dyads) and calcium (7 articles, 714 dyads). HM iodine, manganese, calcium, and zinc concentrations were positively associated with several outcomes (each in ≥2 studies), whereas magnesium (in a single study) was negatively associated with linear growth during early lactation. However, few studies measured HM intake, adjusted for confounders, provided adequate information about complementary and formula feeding, or adequately described HM collection protocols. Only 4 studies (17%) had high overall quality scores. The biological functions of individual HM micronutrients are likely influenced by other HM components; yet, only 1 study analyzed data from multiple micronutrients simultaneously, and few addressed other HM components. Thus, available evidence on this topic is largely inconclusive and fails to address the complex composition of HM. High-quality research employing chronobiology and systems biology approaches is required to understand how HM components work independently and together to influence infant growth and to identify new avenues for future maternal, newborn, or infant nutritional interventions.