Human Breast Milk พญ.วรางค์ทิพย์ คูวุฒยากร พญ.วรางค์ทิพย์ คูวุฒยากร หน่วยทารกแรกเกิด ภาควิชากุมารเวชศาสตร์ คณะแพทยศาสตร์ มหาวิทยาลัยเชียงใหม่

Questions Why breast milk is the best? How milk is produced ? What are human breast milk compositions? Does it different from cow’s milk? What are protective components in human breast milk?

Benefits of breastfeeding

Effect of breastfeeding on the mothers Decrease postpartum hemorrhage Decrease breast , ovarian and endometrial cancer Decrease osteoporosis More rapid return to pre-pregnancy weight

Decrease infection in children Diarrhea ถ่ายเหลว Respiratory tract infection ติดเชื้อทางเดินหายใจ Otitis media หูชั้นกลางอักเสบ Bacteremia ติดเชื้อแบคทีเรียใน กระแสเลือด Bacterial meningitis เยื่อหุ้มสมองอักเสบจาก แบคทีเรีย Urinary tract infection ติดเชื้อทางเดินปัสสาวะ Late onset sepsis in ติดเชื้อในกระแสเลือด preterm infant ในทารกก่อนกำหนด Necrotizing Enterocolitis ลำไส้เน่าเปื่อย from American Academy of Pediatrics. Breast feeding and the use of human milk:Pediatrics.2005;115(2):506 from AAP.Breast feeding and the use of human milk:Pediatrics.2005;115(2):506

Decrease non-infectious disease Asthma หอบหืด Overweight and obesity โรคอ้วน Insulin dependent DM (type I) เบาหวาน Non insulin dependent DM (type II)เบาหวาน Hypercholesterolemia ไขมันสูง Lymphoma มะเร็งต่อมน้ำเหลือง Leukemia มะเร็งเม็ดเลือดขาว Hodgkin disease มะเร็งต่อมน้ำเหลือง Sudden Infant Death Syndrome (SIDs) from American Academy of Pediatrics. Breast feeding and the use of human milk:Pediatrics.2005;115(2):506

Neurodevelopment Anderson JW, Johnstone BM, Remley DT, 1999 Meta-analysis 20 studies Significantly higher levels of cognitive function were seen in breast-fed than in formula-fed children at 6–23 mo of ages Higher IQ 3.16 points in term (95%CI 2.15,3.17) Higher IQ 5.18 points in preterm (95%CI 3.59,6.77) American Journal of Clinical Nutrition, Vol. 70, No. 4, 525-535, October 1999

WHO and UNICEF Infants should be exclusively breastfed for the first six months of life to achieve optimal growth, development and health Infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues for up to two years of age or beyond. “กินนมแม่เพียงอย่างเดียวจนถึงอายุ 6 เดือน หลังจากนั้นกินนมแม่ควบคู่กับอาหาร เสริม จนถึงอายุ 2 ปีหรือมากกว่า “ http://www.who.int/nutrition/topics/infantfeeding_recommendation/en/index.html

Contraindications to breastfeeding HIV positive mother HTLV type I and II positive Active tuberculosis disease Herpes simplex infection on a breast Drugs of abuse Expose to radioactive materials Receiving diagnostic or therapeutic radioactive isotropes Receiving antimetabolites or chemotherapeutic agents AAP.Breast feeding and the use of human milk:Pediatrics.2005;115(2):506 American Academy of Pediatrics .Breast feeding and the use of human milk. Pediatrics 2005;115(2):506

Exclusive breastfeeding is defined as no other food or drink, not even water, except breast milk (including milk expressed or from a wet nurse) for 6 months of life, but allows the infant to receive ORS, drops and syrups (vitamins, minerals and medicines). ให้ทารกกินนมแม่อย่างเดียวโดยไม่ให้อาหารอื่นๆแม้แต่น้ำ เป็นระยะเวลา 6 เดือน ยกเว้นน้ำเกลือแร่ ยา หรือ วิตามินเสริม

อัตราการเลี้ยงลูกด้วยนมแม่ อย่างเดียว 6 เดือน ระหว่างประเทศ ร้อยละ แหล่งที่มา : สำนักนโยบายและยุทธศาสตร์ กระทรวงสาธารณสุข

เปรียบเทียบกับทั่วโลก อัตราการเลี้ยงลูกด้วยนมแม่อย่างเดียว 6 เดือน ประเทศไทยจัดอยู่ในกลุ่มที่มีอัตราน้อยกว่าร้อยละ 20 (สีแดง)

แผนภูมิแสดงการกินนมแม่ของเด็กไทย ปี 2548-2549

Anatomy of the breast

Anatomy of the breast

Mammary development Embryogenesis Pubertal development Mature GH, estrogen Pubertal development progesterone Mature progesterone, prolactin, HPL The Lactation cycle Pregnancy Involution progesterone, prolactin, HPL Prolactin, oxytocin Lactation

Mammary development

Lactogenesis I & II

Lactogenesis II- Prolactin

Anatomy of the breast

Lactogenesis II- Oxytocin

Cellular mechanisms for milk synthesis and secretion Exocytosis Most of the components of the aqueous fraction eg. Protein- casein, CHO- lactose Fat synthesis and secretion Transport across apical membrane Ions and water Transcytosis of interstitial molecules Immunoglobulin A Paracellular pathway

The pathway of milk synthesis and secretion

Colostrums, transitional and mature milk 1-4 day after parturition Transitional milk 4-10 days after parturition Mature milk After 10 days

Colostrums, transitional and mature breast milk

Colostrums ingredients

Breastmilk Composition

Composition of breastmilk

Carbohydrate in human milk Mainly carbohydrate is lactose Increasing amount correlate with milk volume Provides galactose A sugar involved in brain and nervous system development Low risk of causing dental caries

Fat in human milk 30-50 g/L, 97-98% is triglyceride Major energy for a baby (45-55% of total calories) Synthesis and development of retinal and neural tissues Essential fatty acid (FAs) Linoleic acid (8-17%) α-Linolenic acid (0.5-1.0%) Arachinodic acid (0.5-0.7%) (LC-PUFA) Docosahexaenoic acid (0.2-0.5%) (LC-PUFA) Fat digestion is aids by gastric lipase and bile-salt dependent lipase in human milk

Factors influencing human fat content and composition Duration of gestation Stage of lactation Parity volume feeding Maternal diet Maternal energy status Influence BM of the mother who deliver preterm infant has more LC-PUFAs PL and Cholesterol are highest in early lactation High parity is associated with reduced endogenous FA synthesis High volume is associated with low milk fat content Human milk fat content progressively increases during a single nursing A diet low in fat increase endogenous synthesis of MC-FA High weight gain in pregnancy is associated with increased milk fat

Foremilk vs Hindmilk

Protein in Human milk 15.8 g/L (colostrums)  9.0 g/L (mature milk) Whey : Casein = 60 :40 Total protein Protein nitrogen Non-protein nitrogen (20-25%) free amino acid, Carnitine, taurine, Aminosugars Nucleic acids, nucleotides Polyamines

Human milk protein functions Growth Protective factors Carries for vitamins and hormones Enzyme activities Biological activities

Vitamins in human milk Corresponding to maternal status Fat soluble vitamins Vitamin A (200-300 mg/L) Decreases with advancing lactation Vitamin D (0.1-1.0 ug/L) Maternal intake, sunlight, northern latitudes Supplement vitamin D 10 ug/L is recommended in a baby at risk

Fat-Soluble vitamins Vitamin K (1-9 ug/L) Tran placental transfer is minor Maternal dietary intake bears little relationship to milk vitamin K content Maternal supplementation of 5-20 mg/day increases in milk and infant plasma levels

Water-Soluble vitamins Vitamin C (100 mg/L) 8-10 fold higher than the maternal plasma concentration Vitamin B6 Low levels in mothers with a long-term history of OCT uses

Water-Soluble vitamins Vitamin B12 Vitamin B12 deficiency was found in infants nursed by mothers who were strict vegetarians Folate Interfere by maternal diet and medication

Minerals and trace elements in human milk Not correlate with amounts in the maternal diet or maternal serum Calcium, phosphorus and magnesium Sodium, potassium and chloride Iron (0.3mg/L), copper and zinc Iron from HM is absorbed 5-fold more efficiently Lactoferrin

Immunomodulating agent Affect the development of newborns’ immune system cytokines Enhance inflammation TNF-α, IL-1, IL-6, IL-8, interferon-γ Suppress inflammation IL-10 Soluble receptors TNF-α1, TNF-α2

Anti-inflammatory components Antioxidants: vitamins A, C, E Enzymes : catalase, glutathione peroxidase E prostaglandins Enzymes inhibitors: Platelet Activating Factor (PAF) Protease inhibitor Anti-inflammatory cytokine: IL-10

Hormones and growth factors Higher in early mammary secretion (colostrum) Some hormones are synthesized in mammary cells, transfer from maternal circulation or modified by mammary cells Mammary synthesis : PRL, GnRH, thyroxine(T4), Triiodothyronine(T3), PTH-rP, estrogen Transfer from maternal circulation : TRH, progesterone Modified by mammary cell : increase resistance to digestion in infants’ GI tract : PRL Growth factors stimulate GI growth in the newborn

Enzymes in human milk Protective function Digestive function Lysozyme Peroxidase Antiprotease, catalase, glutathione peroxidase, PAF-acetylhydrolase Digestive function Amylase Bile salt-stimulate lipase

Comparison of the macronutrient contents of human milk and bovine milk Component Human milk Bovine milk Carbohydrate (g/dL) Lactose Oligosaccharides 7.3 1.2 4.0 0.1 Protein (g/dL) Caseins α-lactalbumin Lactoferrin Secretory IgA β-lactoglobulin 0.2 2.6 Trace 0.5 Lipids (%) Triglycerides Phospholipids 0.04 From Neville MC.Physiology of lactation.Clin Perinatol1999;26:257

Comparison of the macronutrient contents of human milk and bovine milk Component Human milk Bovine milk Minerals and others(nM) Sodium Potassium Chloride Calcium Magnesium Phosphate Bicarbonate 5.0 15.0 7.5 1.4 1.8 6.0 15 43 24 30 5 11 From Neville MC.Physiology of lactation.Clin Perinatol1999;26:257

Protective factors in human milk

Protective nutrients in human milk Amount Function Protein sIgA IgM IgG Lactoferrin Lysozyme α-lactalbumin casein 50-100 mg/dl 2 mg/dl 1 mg/dl 100-300 mg/dl 5-25 mg/dl 200-300 mg/dl Immune protection Anti-infective, iron carrier Anti-infective Iron carrier (Ca2+), part of lactose synthase Iron carrier, inhibit microbial adhesion to mucosal membrane

Protective nutrients in human milk Amount Function Carbohydrate Lactose Oligosaccharides Glycoconjugates 6.5-7.3 g/L 1.0-1.5 g/L - Energy source Microbial ligands Microbial and viral ligands Fat Triglyceride LC-PUFA FFA 3.5-4.5 g/L Essential for brain and retinal development and for infant growth Anti-infective

Immune protection SIgA – secretory immunoglobulin A is the main component Protects mucosal surfaces eg digestive and respiratory tract Composed of specific antibodies against bacteria that mother has encountered in the environment Includes specific antibodies against diarrhea: giardia, toxigenic E coli, Vibrios, Campylobacter

Enteromammary Immune system

Secretary IgA

Secretary IgA

Non immune protection Broad spectrum of anti-infective activity Lactoferrin Single-chain glycosylated protein 692-amino-acid 79 -kD

Protective function of Lactoferrin neutrophil macrophage Lactoferrin Airway Epithelium Respiratory Tract CD14-TLR4 complex LPS Anti-Inflammatory Bacterial Killing Pseudomonas Pseudomonas Biofilm Anti-Biofilm HIV, CMV Anti-Viral Candida Fungicidal  Rogan et al. Respiratory Research 2006 7:29

Lysozyme 130-amino-acid- containing glycoprotein Hydrolyzes the 1-4 linkage between N- acetyl glucosamine and N-acetylmuramic acid Lyses mostly gram positive and few gram negative bacteria Increases with prolong lactation

K-casein Antiadhesive Casein macropeptide H. pylori, S. pneumoniae, H. influenzae Casein macropeptide Strong growth promoting factor for B. bifidum

α-lactalbumin Important whey protein in BM 3 polypeptide fragments were recently found to have antimicrobial activity These peptides are generated after exposure to protease in GI tract E.coli, K. pneumoniae, S. aureus, S. spidermidis C.albican

Glycoconjugates and oligosaccharides Structure Distribution in milk Function Oligosaccharides Skim milk Protect against heat stable E.coli enterotoxin, attachment of H.influenzae and S.pneumoniae to respiratory epithelium, v.cholerae hemagglutinin activity Glycoproteins Mucin Lactadherin MFGM/ skim milk MFGM MFGM/skim milk Prevent binding of V.cholerae Prevent binding of S.fimbriated E.coli Prevent binding of Rotavirus Gangliosides Receptor analogs for heat labile toxin of V.cholerae and E.coli Glycosaminoglycan Inhibits binding of HIV gp 120 to CD4 receptors

How oligosaccharides block attachment of bacteria to epithelial cells

Lipid Milk fat globules protect infants from infection by The membrane glycoconjugates acts as specific bacteria and viral ligands FFA have a detergent like lytic action on enveloped viruses (HIV, HSV type I), bacteria , fungi and protozoa

Comparison human & cow’s milk