Early Nutrition and Brain Development: General Principles

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The Composition of Breast Milk: Does
Maternal Diet Matter?
Michael K. Georgieff, M.D.
Professor of Pediatrics and Child Development
Director, Center for Neurobehavioral Development
University of Minnesota
Overview
 Role of Breast Milk in Infant Nutrition
 Classes of Nutrients
 Mechanisms of Maternal->Milk Transport
 Milk Volume
 Macronutrients
– Transport; IOM Recommendations
 Selected Micronutrients
– Transport; IOM Recommendations
 Vitamins
– Transport; IOM Recommendations
Role of Breast Milk in Infant Nutrition
 Human Breast Milk is the Gold Standard for
human nutrition
 Usually, complete nutrition for first 6 months in
term infants
– Vitamin D
– Iron
 Preferred base for feeding preterm infants
– Reduction of NEC rates
– Needs fortification
Classes of Nutrients
 Water (volume)
 Macronutrients
– Carbohydrate
– Fat
» LC-PUFAs
 Minerals
– Sodium, Potassium, Chloride, Calcium
 Selected Micronutrients
– Iron, Zinc, Copper
 Vitamins
– Water Soluble (C, Bs, Folate)
– Fat Soluble (A,E,D,K)
Mechanisms of Maternal Milk Production
 Nutrients transported across single cell layer from maternal
serum into milk
– Mammary Epithelial Cell
 Transport can be passive or active based on
– Nutrient
– Developmental time period
 Active transporters similar to those found at other single cell
transport surfaces
– Placenta, intestine, blood-brain barrier
– Typically involve
» Transporter from maternal serum into MEC (apical)
» Exporter from MEC to milk (basal)
The Mammary Epithelial Cell
Water (Volume)
Water (Milk Volume)
 Water is a nutrient!
– Important for metabolic processing
– Consumed and produced by numerous enzymatic processes
 Low milk volume a common cause of lactation failure
– Premature delivery
– Intrauterine growth-retardation (maternal hypertension)
 Milk volume not a function of maternal hydration
(within reason)
– Drinking more water doesn’t help
 Milk volume is a function of amount of lactose
secreted by MEC
Water (Milk Volume)
 Mammary epithelial cell assembles and secretes
lactose
 Water (milk volume) follows osmotically
 Strategies to increase lactose production and
secretion lead to increased milk volume
– Growth hormone administration
– Diet manipulations (increased CHO intake)
» Does not work in non-fasting state
– Genetic variability (polymorphisms of CHO metabolism)
Macronutrients
Carbohydrates
Fat
Macronutrients: Carbohydrates
 Current recommendation is for an additional 400 Kcal/day for lactating
mothers
– No recommendation re: carbohydrate/fat ratio
 Lactose is the primary carbohydrate in mother’s milk
 Dietary lactose is broken down by intestinal lactase into glucose and
galactose
– No circulating lactose in mother’s blood
 Milk lactose must be synthesized from serum glucose and galactose
– “Hexoneogenesis” (Sunehag et al, 2002, 2003)
– Source of glucose and galactose are serum glucose, glycerol and dietary
galactose
Macronutrients: Carbohydrates
 In fed (non-fasting state), 98% of glucose and 68% of galactose that
ends up as lactose in milk is derived from plasma glucose
 After 24 hour fast, percentages derived from plasma glucose drop to
72% and 51% respectively
– Mammary cells use glycerol as source of carbon molecules
 Dietary galactose contributes 7 and 12% respectively if provided.
 Conclusion: Dietary state and CHO intake matters, but unclear if it
matters much in fed state. Adaptations appear important for survival
Sunehag et al, 2002,2003
Macronutrients: Fat
 Fat is main source of calories in human milk (@55%)
– Rat milk is low fat
– Seal milk is up to 95% fat calories!
 Fat content varies considerably (Koletzko et al, 1992)
– Between women of different cultures/diets
» Chinese (hi CHO, low fat) < Swedish (hi fat, low CHO)
– Between women of same culture/diet
» Urban < Rural South African Women
– Within women over time
 No specific IOM recommendations for fat amount or fat
source during lactation
Macronutrients: Fat
 Fats are assembled and transported into milk fat globules
 Fat quantity and quality in diet does influence milk fat content
– Low fat diet causes MEC to synthesize more fat (6x)
» Mostly C10, C12 and C14 species
– DHA supplementation increases DHA content of milk
 Fat Source does influence milk fat concentration
– Animal source vs vegetable source dietary fat
– Role of trans fatty acids (TFAs) and conjugated linoleic acid
(CLAs)
Macronutrients: Effect of Dietary Fat Content
 Partially hydrogenated vegetable oil (high TFAs) found in
processed foods (some margarines)
 McGuire fed one of three diets to lactating mothers;
measured fat content of milk
– High PHVO margarine, low PHVO margarine or low
PHVO butter
– In obese women, diet made no difference
– In lean women, diet made large difference
» Mothers fed high PHVO margarine made 2% milk
» Mothers fed butter or low PHVO margarine made 3.5%
milk (essentially whole milk)
Macronutrients: Specific Fats
 Long Chain Polyunsaturated Fatty Acids
– Docosohexanoic Acid (DHA) production is rate limited in neonates
– Essential fatty acids for preterm and probably term infants
– Necessary for cell membranes in all organs
– Important for visual system and brain development
– Transported
» Across placenta
» Into human milk
» Assures constant flow of LC-PUFA to young human
Influence of Country of Origin on Milk DHA
(Innis et al, 1992)
Country/Culture
% Milk fat as DHA
Inuit Eskimo
1.4
Dominica
0.9
Malaysia
0.9
St. Lucia
0.7
Canada/Vancouver
0.4
Australia
0.35
Sweden
0.30
USA
0.25
Germany
0.2
Maternal Diet Influences
LC-PUFA Content of Human Milk
 DHA supplementation to late gestation and lactating
women works
 Boris et al (2004) fed mothers high DHA fish oil or low
DHA olive oil
– Milk content of DHA in fish oil supplemented women at 4, 16 and
30 days was 2.3, 4.1 and 3.3 times higher than olive oil
supplemented
 Henderson et al (1992) supplemented lactating women
with 6 g/d of fish oil for 21 days
– Milk DHA increased from 0.37% to 0.70% of total fat (by weight)
Minerals
Sodium
Potassium
Chloride
Calcium
Minerals
 Major minerals are sodium, potassium, chloride
 Determined largely by osmotic forces (milk
volume)
– Active Na and K pumps
 Na, K, Cl are determined by electrical gradient in
secretory cells and not affected by maternal diet
 No specific IOM recommendations for these
minerals
Calcium
Calcium transported actively, but
mechanisms are poorly understood
Maternal diet does not influence milk
calcium concentrations
– Does not appear that drinking more milk,
calcium supplements alter MEC excretion of
calcium into milk
Different than Vit D, where maternal diet
makes a difference
Calcium: IOM AI for Daily Calcium Intake
by Lactating Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
1300 mg
1000 mg
1300 mg
1000 mg
Source: IOM DRIs, 2001
Micronutrients
Independent of Mom: Fe, Zn, Cu
Dependent on Mom: Se, I, Fl, Mn
Vectoral Micronutrient Transport by MEC
Milk
Maternal Blood
Intracellular
Unloading
Nutrient
(maternal)
Importer Receptor
(TfR, Zip3,Ctr1)
Exporter
(FPN, Znt,
Nutrient
ATP7)
2+
4 Fe
Transporter
Endosome
Binding Protein
Nutrient
Protein binding
Nutrient
(fetal)
Micronutrients: Iron
 Breast milk quite low in iron concentration
compared to formula (0.3 to 0.5 mg/L vs 4.5 to 12
mg/L)
– More bioavailable (50% vs 4-33%)
 Iron transported actively across MEC using typical
transporters
– Transferrin Receptor (uptake from serum)
– Divalent Metal Transporter-1 (off loading intracellularly)
– Ferroportin (export to milk)
Picture of Iron transport in MEC
Kelleher and Lonnerdal, 2005
Iron: Does Maternal Diet Matter?
 Iron deficient mothers produce iron sufficient milk
– Unclear if iron deficiency increases transporter expression to maintain
milk iron content (as seen with intestine and placenta)
 However, no evidence in humans that increased iron
intake influences milk iron content
– Likely due to highly regulated iron transport process
» Iron sufficiency decreases activity of iron transporters
» Protects from iron overload in other systems
– In rats, increased maternal dietary iron does increase maternal milk
iron
 More research needed
IOM RDA for Iron Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
15 mg
18 mg
10 mg*
9 mg*
* Assumes that lactation inhibits menstrual cycle
Source: IOM DRIs, 2001
Micronutrients: Zinc
 Milk zinc concentrations decrease over duration of
lactation
– Drop rapidly after 6 months
 Zinc is actively transported across MEC
– Zip family of transporter for uptake from maternal serum
– ZnT families of transporters for secretion into milk
 Zinc content of milk not influenced by maternal
diet
Picture of Zinc transport in MEC
Kelleher and Lonnerdal, 2005
IOM RDA for Zinc Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
8 mg
8 mg
13 mg
12 mg
Source: IOM DRIs, 2001
Micronutrients: Copper
 Milk copper concentrations decrease over duration
of lactation
– Drop rapidly after 6 months
 Copper is actively transported across MEC
– CTR1 transporter for uptake from maternal serum
– ATP7a transporter for secretion into milk
 Copper content of milk not influenced by maternal
diet
Picture of Copper transport in MEC
Kelleher and Lonnerdal, 2005
IOM RDA for Copper Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
1300 mcg 1300 mcg 900 mcg
Lactating
18-50 years
900 mcg
Source: IOM DRIs, 2001
Micronutrients That are Dependent on
Maternal Serum Concentration
 Se, I, Fl, Mn are related to maternal intake
 Selenium
– Necessary for normal iodine/thyroid status
 Iodine
– Necessary for normal thyroid status
 Fluoride
– Necessary for bone/teeth
– No studies of metabolism of fluoride during lactation
 Manganese
– Necessary in enzymatic reactions (metabolism)
IOM Recommendations for Selenium, Iodine,
Fluoride and Manganese during Lactation
Nutrient
Nonlactating
18-50y
55 mcg
Lactating
14-18y
Lactating
18-50y
Selenium
Nonlactating
14-18 y
55 mcg
70 mcg
70 mcg
Iodine
150 mcg
150 mcg
290 mcg
290 mcg
Fluoride
3 mg
3mg
3mg
3mg
Manganese
1.6 mg
1.8 mg
2.6 mg
2.6 mg
Source: IOM DRIs, 2001
Selected Vitamins
Folate
B6
B12
Vitamin A
Vitamin D
Three Patterns of Maternal Status-Milk Status Relationship
Courtesy of Kay Dewey
Folate
Necessary for
– 1-carbon metabolism, cell division
– Neurodevelopment
» Neural tube closure (peri-conceptional)
» Cognitive development (late fetal, neonatal)
Actively transported from mother to fetus
Maternal diet does not affect milk unless
mom very deficient
IOM RDA for Folate Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
400 mcg
400 mcg
500 mcg
500 mcg
Source: IOM DRIs, 2001
Vitamin B6
Low B6 levels associated with
– Abnormal maternal and infant behaviors
– Slower growth, especially after 4-6 months
Maternal diet influences B-6 levels
– India
– USA
IOM RDA for B6 Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
2 mg
2 mg
1.2 mg
1.3 mg
Source: IOM DRIs, 2001
Vitamin B12
Low meat intake causes low B12 in milk
 High prevalence in developing countries
– 32% in Guatemalan lactating women
 Increased risk in subpopulations of developed countries
– Maternal avoidance of animal source foods x 4 years causes low milk B12
– Vegan mothers
 Effect on behavior and motor development in offspring
– Mechanism unknown
IOM RDA for B12 Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
2.4 mcg
2 mcg
2.8 mcg
2.8 mcg
Source: IOM DRIs, 2001
Vitamin D, Breastfeeding and Rickets
Rickets thought to be disease of the past
– “Disappeared” in early 1960s due to:
»
Recognition of role of sunlight in vitamin D
homeostasis; fortification of milk
»
Use of multivitamin preps
Higher prevalence of formula use
» AAP CON recommended 200 IU/d starting at 2
weeks of age
»
Prevalence: Is This A Real Problem?
 Case reports of nutritional rickets pop up in late 1970s
 Increased case reports in last 20 years
 Exact prevalence remains unknown but prevalence of risk
factors increasing
– Less sun exposure
– Higher prevalence of nursing
– Decreased prescription of vitamins for nursing infants
Milk Content of Vitamin D
 Human milk (22 to 100 IU/L)
– Varies with maternal diet, pigmentation/sun exposure
– Light pigmentation 68 IU/L
– Dark pigmentation  35 IU/L
– Both fall far short of RDA/DRI (infant does not consume
1L until 14 lbs=5-6 months of age)
– Maternal 3000 IU/d supplement-> 100 IU/L
– New data from Bruce Hollis’ group-> Maternal
supplementation with 10,000 IU/d is safe and keeps
infants vitamin D sufficient
» Not in practice yet pending larger study
IOM AI for Vitamin D Intake by Lactating
Mothers
Non-lactating
14-18 years
Non-lactating
18-50 years
Lactating
14-18 years
Lactating
18-50 years
200 IU
200 IU
200 IU*
200 IU*
Source: IOM DRIs, 2001
Summary of Micronutrient Groups in Lactation
Group I
Group II
Milk concentration correlated with maternal Milk concentration relatively independent
status, infant rapidly depleted. Supplements of maternal status, mother may become
depleted. Supplements have little or no
 level in milk.
effect on milk level.
Examples: Thiamin
Riboflavin
Vitamin B-6
Vitamin B-12
Vitamin A
Iodine
Selenium
Examples: Folate
Calcium
Iron
Copper
Zinc
Table courtesy of Dr. Kay Dewey
Summary: Clinical Implications
Some nutrients in human milk are not influenced by
maternal diet unless the mother is very deficient;
supplementation of sufficient mother doesn’t change milk
Some nutrients are highly dependent on maternal diet
Milk volume can potentially be increased by increasing
carbohydrate content of milk
– No clinical strategy to do this yet
Summary: Clinical Implications
Milk fat content and composition highly influenced by
maternal diet
– Butter vs margarine? Ice cream?
– Fish oil vs vegetable oil to increase DHA
Iron, zinc and copper all become very low after 6
months of lactation
– Argument to start complimentary food
Low meat consumption places B12 at risk
Maternal supplementation with high dose Vitamin D
may get around supplementing infant (AAP rec.)
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