Infant Feeding: Human Milk and Formula

Infant Feeding: History and Perspective Human Milk Human Milk Substitutes Science, Medicine and Industry

Feeding the Infant Considerations – Infant (needs, tolerance, acceptance, safety) – Family preferences – Cost and availability – Prevention, health, development, and programming

Feeding the Infant Choices: – Human Milk – Standard Infant Formula (Cow, Soy) – Hypoallergenic (hydrolysates vs. amino acid based – Other specialty formulas – Beikost/solids/table foods

History Human milk substitutes Health and welfare Programs Formula Industry

Human Milk Substitutes Early evidence of artificial feeding Majority of infants received breast milk – Maternal BF – Wet nurses Wealthy women Orphans, abandoned, “illegitimate” Prematurity or congenital deformities

Wet Nurses Work demands, societal needs, vanity, health requirements, social diversion Proper selection: Questionable character--  Infant would suck in her vices Wet Nurse Industry: emerging infant mortality/abuse Impact of industrial revolution: Wet nurses made better money in factories

Human Milk Substitutes: Infant Mortality Artificial feeding in first weeks of life associated with 100% mortality 19 th century infant mortality with “hand feeding” was 88% Foundlings: 80% In Dublin Foundling hospital : 99.6%

Science, Medicine, and Industry Growth of child Health and welfare in early 20 th century

Science, Medicine, and Industry Infant Morbidity and Mortality Recognition of association with human milk substitutes, and infection Industrial development – Storage – Safety – Food industry

Human Milk Substitutes ’s: evaporated or fresh cow’s milk, water and added CHO (prepared at home) 1950’s to present commercially prepared infant formulas have replaced home recipes

Infant Formulas - History Cow’s milk is high in protein, low in CHO, results in large initial curd formation in gut if not heated before feeding Early Formulas – from majority of non-breastfed infants received evaporated milk formulas boiled or evaporated milk solved curd formation problems – cho provided by corn syrup or other cho to decrease relative protein kcals

Historical timeline 1900 – Pasteurization of milk in US – Association between bacteria and diarrhea 1912 – U.S Children’s Bureau – Public Health and Pediatricians efforts to improve infant/child health and decrease mortality 1920 – Intro evaporated milk – Cod liver oil prevents rickets – Curd tension of milk altered – Increased availability of refrigeration – Vitamin C isolated – Vitamin D prepared in pure form – Improved sanitation

Historical timeline 1940 – Homogenized milk widely marketed 1960 – Further advances in technology and packaging – Commercially prepared infant formula becoming increasingly popular

Interesting Milestones in Infant Nutrition 1784: Underwood recommends cows milk as alternative to breast feeding 1800: glass feeding bottles 1838: Simon determines protein CM>BM 1845: Pratt patents rubber nipple 1856: Borden patents condensed milk 1883: Meyenberg patents evaporated goats milk 1885: Meigs analyses human milk

Interesting Milestones in Infant Nutrition 1911: MJ introduces Dextri-maltose 1915: SMA 1920: Franklyn (Similac) 1929: MJ markets Sobee, hypoallergenic : Concentrated liquid, hydrolysed, elemental, and ready to feed formulas introduced What now?

Interesting Milestones in Infant Nutrition 1911: MJ introduces Dextri-maltose 1915: SMA 1920: Franklyn (Similac) 1929: MJ markets Sobee, hypoallergenic : Concentrated liquid, hydrolysed, elemental, and ready to feed formulas introduced What now?

Infant Formula - History, cont. 50s and 60s commercial formulas replaced home preparation 1959: iron fortification introduced, but in 1971 only 25% of infants were fed Fe fortified formula Cow’s milk feedings started in middle of first year between s. In 1970 almost 70% of infants were receiving cow’s milk.

“No two hemispheres of any learned professor’s brain are equal to two healthy mammary glands in the production of a satisfactory food for infants” - Oliver Wendell Holmes

Human Milk Complements infant Immaturity Promotes maturation – Epithelial growth factors and hormones – Digestive enzymes - lipases and amylase

Characteristics and Advantages of Human Milk Low renal solute load Immunologic, growth and trophic factors – Decrease illness, infection, allergy Improved digestion and absorption Nutrient Composition: CHO, Protein, Fatty Acid, etc Cost Other

Human Milk Colostrum – Higher concentration of protein and antibodies – Transitions around days 3-5 – Mature by day 10

Human Milk Nutrient composition of human milk is remarkable for its variability, as the content of some of the nutrients change during lactation, throughout the day, or differ among women, while the content of some nutrients remain relatively constant throughout lactation.

Role of Human Milk Components in GI Development: Current Knowledge and Future Needs: Donovan J Pediatr 2006:149:S49-S61 “ existing clinical and epidemiological studies support a developmental advantage for breastfeeding. However, our understanding of the mechanisms by which HM components exert their actions within the human infant are limited by the large number of bioactive compounds in milk and the complexity of the potential interactions among the components and with the developing intestine”

Human Milk Compartments Aqueous Phase – Ca, Mg, Ph, Na, Cl, CO2, casein proteins, whey proteins (lactoalbumin, lactoferrin, IgA, lysozyme, albumin) Lactose, amino acids, water soluble vitamins Colloidal Dispersion – Caseins, Ca, Ph Fat emulsion – Fat (phospholipid, TG, cholesterol) protein as fat globule membrane, enzymes, trace minerals, fat soluble vitamins, macrophages, neutrophils, lymphocytes

Milk Synthesis Mammary gland contains stem cells and highly differentiated secretory alveolar cells at the terminal ducts. Stimulated by insulin and HGH synergized by prolactin, these cells are active in milk synthesis and secretion

Milk synthesis and secretion Exocytosis ( protein, lactose, Ca/Ph, citrate) Fat synthesis ( TG synthesized in cytoplasm and smooth endoplasmic reticulum + precursors imported from maternal circulation): alveolar cells synthesize SCFA Secretion of ions and water Immunoglobins transferred from extracellular spaces

Paracellular Pathway (5 th process) The paracellular spaces between alveolar cells normally prevent transfer secondary to tight junctions. If these spaces become “leaky” plasma constituents may pass directly into the milk.

Milk Synthesis and secretion Under neuroendocrine control that varies with timing and stage of lactation – Prolactin – Lactogens – Estrogen – Thyroxine – Growth hormone – ACTH – other – Stimulus: infant suckling

Milk synthesis Protein:vast majority of proteins present in human milk are specific to mammary secretions and not identified in any quantity elsewhere in nature: – Immunoglobins transferred from plasma in early stages of lactation – De novo protein synthesis by mammary gland

Diet, milk production, and milk composition There is a great variation in milk composition during a feed, from feed to feed, and even between breasts. The impact of dietary variation and milk composition is unclear. Overall milk composition remains relatively unaffected by diet variations although there are reports to the contrary: – DHA and ARA supplementation, vegan diet, drugs and environmental contaminants,…..

Breast milk composition and Diet DHA levels of breast milk vary with diet. Increased amounts of DHA have been found in the breast milk of mothers consuming fish or fish oil, and with supplementation. Water soluble vitamins may vary with diet. Diets inadequate in B12 or thiamin have been associated with case reports of deficiency in infants. High intakes of Vitamin C, however, does not appear to change the content of breast milk. Supplementation of fat soluble vitamins do not appear to alter the content of breast milk Iron supplementation does not appear to alter the iron content of breast milk

Influence of diet on milk composition Protein-energy malnutrition impacts milk volume. Composition remains relatively unaffected Water soluble vitamins move readily from serum to milk thus dietary fluctuations are more apparent – B12 vegan, case report of beriberi ….. Fat soluble vitamin content not improved with supplementation Fatty acid composition (DHA and ARA) altered by maternal diet and supplementation

Science and Lactation: Frank Hytten “ In general, it is probable that the breast has a high priority for nutrients and that moderate maternal under nutrition will have little effect on milk production. But severe malnutrition, which rarely exists without associated ill- health and other adverse circumstances, may reduce milk yield”

Distribution of Kcals: Breast milk

Protein: Predominant protein of human milk is whey. Casein/whey ratio is between 40:60 and 30:70 – Casein: proteins of the curd (low solubility at pH 4.6) – Whey: soluble proteins (remain soluble at pH 4.6) Lactalbumin Lactoferrin Secretory IgA Lactoglobulin

Carbohydrate Predominant carbohydrate of breast milk is lactose (7.3 g/dl) Oligosaccharides (1.2 g/dl) – Prebiotics: nondigestible CHO that enhance the growth of “favorable” bacteria and contribute to the unique GI bacterial characteristics of BF infant (bifidobacteria)

Fat % Fat (provides approx 50% of calories) Contained in membrane enclosed milk fat globules – Core: TG (98-99%of total milk fat) – Membrane: phospholipids, cholesterol, protein DHA/ARA: wide variations

DHA/ARA concentration variation in human milk DHA: % ARA: % – DHA lowest in populations with high meat intake and highest in populations with high fish intake

Breast milk and establishment of core microbiome Definition: Full collection of microbes that naturally exist within the body. Alterations or disruptions in core microbiome associated with chronic illness: Crohns disease, increased susceptibility to infection, allergy, NEC, etc

Microbiome Beneficial effect for the host: – Nutrient metabolism – Tissue development – Resistance to colonization with pathogens – Maintenance of intestinal homeostasis – Immunological activation and protection of GI integrity

Human milk and microbiome Core microbiome established soon after birth Core microbiome of breastfeeding infant similar to core microbiome of lactating mother Components of breast milk supporting establishment of microbiome – Prebiotics,probiotics

AAP Policy Statement: Breastfeeding and the use of human milk AAP statement includes 15 recommendations on Breastfeeding healthy term infants including: – Establish peripartum policies and practices supporting breastfeeding – Place infant skin to skin after delivery until first feeding is accomplished

AAP Policy Statement:Recommendations continued – Supplements (water, glucose water, formula) should not be given unless medically indicated – Avoid pacifier during initiation (? Recent OHSU report) – 8-12 feedings at the breast every 24 hours during early weeks – All newborn breastfeeding infants should be seen by HCP at 3-5 days and again at 2-3 weeks of age – All breast feeding infants should receive 200 (changed to 400) IU Vitamin D

AAP Policy Statement: Breastfeeding and the use of human milk: Pediatrics 115 # Human milk is species specific and uniquely superior for infant feeding Exclusive breastfeeding is the reference or normative model against which all alternative methods must be measured in regards to growth, development and health Research provides strong evidence that human milk feeding decreases the incidence and/or severity of a number of infectious diseases (meningitis, Otitis media, UTIs, Respiratory tract infections, NEC, diarrhea)

AAP Policy Statement: Breastfeeding and the use of human milk: Contraindications to breastfeeding – Galactosemia – Maternal use/exposure to certain radioactive or chemotherapeutic agents – Maternal abuse of “street drugs” – Active HSV lesions of breast – Maternal HIV (in USA)

AAP Policy Statement: Breastfeeding and the use of human milk: Some studies suggest decreased incidence of SIDS, diabetes (type 1 and 2), leukemia, obesity, hypercholesterolemia, and allergy (asthma and atopy) Breastfeeding has been associated with slightly enhanced performance on tests of cognitive development.

Newborn Visit: Breastfeeding Maternal care – rest – fluids – relieving breast engorgement – caring for nipples – eating properly Follow-up support from the health professional by telephone, home visit, nurse visit, or early office visit.

Cautionary Tales Cooper et al. Pediatrics Increased incidence of severe breastfeeding malnutrition and hypernatremia in a metropolitan area. Rolf et al. ACTA Paediatrica A nationwide study on hospital admissions due to dehydration in exclusively breastfed infants in the Netherlands:its incidence, clinical characteristics, treatment and outcome Lozoff et al. J Pediatrics 2009 Higher Infant Blood Levels with Longer Duration of Breastfeeding

Cooper. 5 breastfed infants admitted to Children’s hospital in Cincinnati over 5 months period for breastfeeding malnutrition and dehydration – Age of admission: 5-14 days – Weight loss at admission 23%, range 14-32% – Serum Na: 186 mmol/L, range ( wnl) – mothers were between the ages of 28 and 38, had prepared for breastfeeding – 3 had inverted nipples and reported latch-on problems before discharge – 3 families had contact with health care providers before readmission including calls to PCP and home visit by PHN

Rolf Survey to determine incidence and characteristics of hospital admission due to dehydration Dutch Paediatric Surveillance Unit of all hospital admissions during 1 st 3 months in fully breast fed infants 250 reported cases. N= 158 (excluded cases with incomplete information or co- existing medical conditions accounting for hospitalization

Lozoff Our findings support the conclusions… “that this phenomenon constitutes a potential public health problem in areas where environmental lead exposure is continuing as well as where environmental lead exposure has recently declined”… Our findings do not detract from the many known benefits of breastfeeding. Rather, they suggest that monitoring lead concentrations in breastfed infants should be considered….

Formula Composition Breast Milk as “gold standard” – Attempt to duplicate composition of breastmilk – ? Bioactivity, relationship, function of all factors present in breast milk – ? Measure outcome: growth, composition, functional indices

Formula Categories Standard – Cows milk base – Soy base Elemental – Hydrolysates – Amino acid pased Other Specialty Products – Metabolics – PM 60/40 – Low fat/MCT – Premature feeding products

Formula Brands Ross – Similac/Isomil/Alimentum Mead Johnson – Enfamil/Prosobee/Enfacare Nestle – Good Start Wyeth – Generic in USA; Gold Brands; SMA SHS – NeoCate, DuoCal

Distribution of Kcals

Vitamin and Mineral content NAS/FDA Meet levels at typical volumes ingested by infants ounces) – i.e. RDA/DRI

Cow’s Milk Based Formula Commercial formula designed to approximate nutrients provided in human milk Some nutrients added at higher levels due to less complete digestion and absorption

Milk Based Formulas Standard 0-12 months – Similac with iron – Enfamil with iron – Good Start Essentials/Good Start Supreme – Wyeth Generic Standard 0-12 mos with DHA/ARA – Similac Advance with iron – Enfamil Lipil with iron – Good Start Supreme DHA/ARA – Wyeth formulas

Protein Blend of whey and casein proteins % total calories – whey proteins of human and cow’s milk are different and have different amino acid profiles. Major whey proteins of human milk are lactalbumin (high levels of essential aa), immunoglobulins, and lactoferrin( enhances iron transportation) Cow’s milk has low levels of these proteins and high levels of b lactoglobulin

Cow’s Milk Based Formula: Fat & CHO Fat: butterfat of cow’s milk is replaced with vegetable fat sources to make the fatty acid profile of cow’s milk formulas more like those of human milk and to increase the proportion of essential fatty acids CHO: Lactose is the major carbohydrate in most cows’ milk based formulas. Meets needs of healthy infants

Milk Based Pre and Probiotic Supplemented Marketed to promote digestive health and support healthy immune fx Probiotic – Bifidus BL Gerber Good start Protect Plus – Lactobacillus rhamosus Nutramigen Lipil with Enflora Prebiotic – Galactooligosaccarides (GOS) – Similac Advance Early Shield (Triple Shield), Enfamil Premium, Generic Brands

Infant Formulas: AAP Cow’s milk based formula is recommended for the first 12 months if breast milk is not available

Soy Formulas First developed in 1930s with soy flour Early formulas produced diarrhea and excessive gas Now use soy protein isolate with added methionine

Soy Formulas Isomil/Isomil DF /Isomil Advance/Isomil Advance 2 Prosobee/Prosobee Lipil/Next Step Prosobee Good Start Essentials Soy/Good Start 2 Essentials Soy Wyeth All iron fortified

Soy Formulas Protein: soy protein isolate with added methionine Fat: vegetables oils CHO: usually corn based products

Soy Formulas Characteristics compared to Milk Based Higher protein (lower quality) Higher sodium, calcium, and phosphorus Carbohydrate: Corn syrup solids, sucrose, and/or maltodextrin; lactose free Fats : Long chain Meet needs of healthy infants

American Academy of Pediatrics Committee on Nutrition. Soy Protein- based Formulas: Recommendations for Use in Infant Feeding. Pediatrics 1998;101: Soy formulas given to 25% of infants but needed by very few Offers no advantage over cow milk protein based formula as a supplement for breastfed infants Provides appropriate nutrition for normal growth and development Indicated primarily in the case of vegetarian families and for the very small number of infants with galactosemia and hereditary lactase deficiency

Possible Concerns about Soy Formulas: AAP 60% of infants with cowmilk protein induced enterocolitis will also be sensitive to soy protein - damaged mucosa allows increased uptake of antigen. Contains phytates and fiber oligosacharides so will inhibit absorption of minerals (additional Ca is added) Higher levels of osteopenia in preterm infants given soy formulas Phytoestrogens at levels that demonstrate physiologic activity in rodent models Higher aluminum levels

Health Consequences of Early Soy Consumption. Badger et al. J Nutr US soy formulas made with soy protein isolate (SPI+) SPI+ has several phytochemicals, including isoflavones Isoflavones are referred to as phytoestrogens Phytoestrogens bind to estrogen receptors & act as estrogen agonists, antagonists, or selective estrogen receptor modulators depending on tissue, cell type, hormonal status, age, etc.

Should we be Concerned? - Badger et al. No human data support toxicity of soyfoods Soyfoods have a long history in Asia Millions of American infants have been fed soy formula over the past 3 decades Rat studies indicate a potential protective effect of soy in infancy for cancer

Contraindications to Soy Formula: AAP – preterm infants due to increased risk of inadequate bone mineralization – infants with cow milk protein-induced enteropathy or enterocolitis – most previously well infants with acute gastroenteritis – prevention of colic or allergy.

Elemental Formulas Hydrolysates Amino Acid Based

Protein Hydrolysate Formulas Alimentum Advance Pregestimil/Pregestimil Lipil Nutramigen Lipil  Protein Casein hyrolysate + free AA’s  Fat (Alimentum and Pregestimil) Medium chain + Long chain triglycerides;(Nutramigen) Long chain triglycerides  Carbohydrate: Lactose free

Hydrolysate Formulas Whey Hydrolysate Formula: Cow’s milk based formula in which the protein is provided as whey proteins that have been hydrolyzed to smaller protein fractions, primarily peptides. This formula may provoke an allergic response in infants with cow’s milk protein allergy. Casein Hydrolysate Formula: Infant formula based on hydrolyzed casein protein, produced by partially breaking down the casein into smaller peptide fragments and amino acids. `

AAP Policy Statement Re: Hypoallergenic Infant Formulas (August, 2000) Recommendations

AAP Policy Statement Re: Hypoallergenic Infant Formulas (August, 2000) Currently available, partially hydrolyzed formulas are not hypoallergenic.

2.Formula-fed infants with confirmed cow's milk allergy may benefit from the use of a hypoallergenic or soy formula as described for the breastfed infant.

Amino Acid Based

Amino Acid Based Formulas Elecare, Neocate, Nutramigen AA  Protein: Free Amino Acids  Fat: Long chain and medium chain  Elecare (33% MCT), Neocate (5% MCT)  Carbohydrate: corn syrup solids, Lactose and sucrose free  Indications for use: Food Allergy or intolerance to peptides or whole protein

Elemental Infant Formula NeoCate (SHS)  Protein: Free Amino Acids  Fat: Long chain  Carbohydrate: Lactose Free  Indications for use: Food Allergy or intolerance to peptides or whole protein

Other Specialty Formulas Similac PM 60/40 (Ross)  Low in Ca, P, K+ and NA; 2:1 Ca:P ratio  Used for infants with Renal Failure Formulas for Metabolic Disorders Preterm Products Low fat high MCT

Indications Cow’s milk based – Health term infant Soy – Vegetarian – Galactosemia Protein Hydrolysates – Protein intolerance/allergy – other Preterm Formulas Post-discharge Preterm formulas Other Specialty Formulas – Specific medical, metabolic indications

Know What You Are Feeding n Caloric density, protein, fat and carbohydrate vitamin and mineral content. n Osmolality: n Renal Solute Load: Evaluate RSL in context of solute intake, fluid intake and output. n Evidence Based n Rationale n Cost and availability

Finding Up to Date Information Similac products Enfamil products Nestle products generic products – lower cost formulas made by Wyeth Neocate formulas

Regulation of Infant Formula FDA – Infant Formula Act Manufacturers – Voluntary monitoring AAP, National Academy of Sciences, other professional organizations – Guidelines for composition and intake: (e.g. DRI’s) – Guidelines for preparation and handling of formula/human milk in health care facilities

Regulation of Infant Formulas Infant Formula Act: – Manufacturing regulations – Quality control Non specific testing requirements, case by case basis, growth outcomes – Recall Proceedures – Nutrient content and labeling – Panel convened 1998 and 2002 (recommended revisions including exemptions)

Regulation of Infant Formulas Infant Formula Act: The purpose of the infant formula act (1980) is to ensure the safety and nutrition of infant formulas – including minimum and in some cases maximum levels of specified nutrients. The act authorizes the FDA to establish appropriate regulations for 1) new formulas, 2) formulas entering the U.S. market, 3) major changes, revisions, or substitutions of macronutrients 4) formulas manufactured in new plants or processing lines, 5) addition of new constituents 6) use of new equipment or technology 7) packaging changes

Formula Regulation Regulation is by the Infant Formula Act of 1980, under FDA authority Nutrient composition guidelines for 29 nutrients established by AAP Committee on Nutrition and adopted as regs by FDA Nutrient Requirements for Infant Formulas. Federal Register 36, CFR Part 107.

Infant Formula Act Institute of Medicine Food and Nutrition Board 3/2004 “Although the federal regulatory processes for evaluating the safety of food ingredients have worked well for conventional substances, they were not designed to ensure the needs and vulnerabilities of infants and are insufficient to ensure the safety of new types of ingredients proposed for infant formulas

Infant Formula Act “ The current regulatory processed do not fully address the unique role of formula as a food source. Formula is the only infants’ food if they are not being breastfed. The processes used to regulate the safety of any new additions of formula should be tailored to these products distict role and the special needs and susceptibilities of infants ”

Infant Formula Act Key limitation: lack of explicit guideleines for determining when and what safety data is needed…..(GRAS) Clarification is crucial given the increasing number of bioactive peptides and enzymens generated from unconventional sources or new technologies

Infant Formula Act: Points for discussion Addition of DHA and ARA to formulas Addition of prebiotics to formula – Present in BM – GRAS – Vitamin/mineral content conforms to regulation – ? testing

Formula safety FDA recall list

Cows milk and goats milk Protein RSL Folic acid, iron, vitamin D pasteurization