DELIVERING LIPIDS AND FATTY ACIDS TO OPTIMIZE GROWTH, DEVELOPMENT & HEALTH

Camilia R. Martin, MD MS
Assistant Professor of Pediatrics, Harvard Medical School Associate Director, NICU, Department of Neonatology Director for Cross-Disciplinary Research Partnerships, Division of Translational Research Beth Israel Deaconess Medical Center, Boston MA IPOKRaTES Clinical Seminar January 26, 2013

Overview

Nutrition & Nutritional Practices

Growth & Long-Term Outcomes

Growth & Short-Term Outcomes

2
Lipids

3
Early Nutritional & Postnatal Intestinal Development

4
Immunonutrients

Objectives
Review current recommendations for lipid delivery
Discuss fatty acid requirements during fetal development Demonstrate postnatal fatty acid alterations resulting from

current neonatal nutritional practices & its impact on health and disease Postulate potential strategies to optimize postnatal fatty acid levels

Lipid: Definition
Organic compound that is readily soluble in nonpolar

solvent but not in polar solvent (e.g water)

Major biological functions involve energy storage,

structural component of cell membrane, and cell signaling.

Examples: sterols, cholesterol, monoglycerides,

diglycerides, triglycerides, and phospholipids

Lipids
Preterm infants have very limited endogenous lipid stores Essential component of parenteral nutrition Serves as a source of Linoleic Acid Necessary to prevent essential fatty acid deficiency (0.5 1.0

gm/k/day) Meets high energy needs: High caloric source at 9 kcal/gm Important source for gluconeogenesis; which, ultimately may also reduce need for increased glucose infusion rates Step-wise advancement starting at 1.0 gm/k/day to goal of 3.5 gm/k/day Monitor triglyceride levels 20% preparation recommended for neonates; improved tolerance over 10% solutions (decrease risk of hypertriglyceridemia, hypercholesterolemia, hyperphospholipidemia)

Triglycerides & Phospholipids

Triglyceride Phospholipid

http://www.chemistryland.com/CHM151W/12-Final/triglyceride.jpg

http://faculty.uca.edu/johnc/phospholipid.jpg

Fatty acid metabolism in the preterm infant

Innis, Neoreviews 2002

Fatty Acid: Definitions

Long hydrocarbon chain capped by a carboxyl group

(COOH)
Saturated: Saturated with hydrogens, every carbon links with the maximum number of hydrogens, thus all single bonds Unsaturated: Not every carbon links with the maximum number of hydrogens, thus some carbon-carbon links are double bonds

Fatty Acid: Nomenclature

Carboxyl group

Terminal Methyl Carbon

18:3 (n-3)

1 3

1. Total number of carbons (c) 2. Total number of double bonds 3. Number of carbon from the terminal methyl end with the first double bond

Fatty Acid: Nomenclature, cont

1. Total number of carbons (c) 22
2. Total number of double bonds 6 3. Number of carbon from the terminal methyl end with the first double bond 3

22:6 (n-3)

DHA

Inflammation

Nucleus

DHA and polyunsaturated fatty acids (PUFAs) are important in: 1. Maintaining the structure of the cell, and 2. Regulating the production of inflammatory proteins

Cell Membrane: A Closer Look

A Intracellular space or cytosol B Extracellular space or vesicle/Golgi apparatus lumen

1. 2. 3. 4. 5. 6. 7. 8.

Non-raft membrane Lipid raft Lipid raft associated transmembrane protein Non-raft membrane protein Glycosylation modifications (on glycoproteins and glycolipids) GPI-anchored protein Cholesterol Glycolipid http://en.wikipedia.org/wiki/File:Lipid_raft_organisation_scheme.svg

PUFA & Systemic Inflammation

LCFA : (1) cellular membranes fluidity and function (DHA most predominant FA in brain) (2) central role in inflammatory cascades

Enke et al. Br J Nutr, 2008

Placental Transport of Fatty Acids

Haggarty, Ann Rev Nutr, 2010

Biomagnification

Haggarty, Ann Rev Nutr, 2010

Fatty Acids & Fetal Organ Development

Lapillonne, et al, 2009

Fatty Acids & In-Utero Accretion Rate

Lapillonne, et al, 2009

Diseases of Extremely Premature Infants

Retinopathy of Prematurity: 40% Long-term cognitive impairment: 35% Chronic Lung Disease: 30-50%

Infection: 20%
Necrotizing Enterocolitis: 5%

What is common to many of these disease? 1. DHA is critical in brain and eye development 2. DHA prevents excessive inflammation

DHA No DHA

IV Fluids
Optimal Growth & Organ Development

1. What happens to DHA levels after premature birth? 2. If low, do they cause disease?
DHA No DHA

Proteins Sugars

IV Fluids
Fat

Optimal Nutrition

Infant Health Research Program

Biorepository: All samples collected & stored Nutritional Blood Fecal Linked to all clinical information

Analyze fatty acids and correlate with disease

Median DHA levels in preterm infants rapidly decline, falling below levels discovered to be present throughout the 3rd trimester
8
Median DHA levels at birth in TERM infants

Median DHA level, mol% 4 5 6 7

Median DHA levels at birth in PRETERM infants

Median DHA levels present throughout the 3rd trimester

3 0
Martin et al, Journal of Pediatrics, 2011

2 3 Postnatal Week (Birth = Week 0)

Similarly, LA and AA levels rapidly change from blood levels discovered to be present throughout the third trimester
20 Linoleic Acid (LA) Median LA and AA levels, mol% 10 15
Median AA levels at birth in PRETERM infants Median AA levels at birth in TERM infants

Median AA levels present throughout the 3rd trimester

Arachidonic Acid (AA)

LA levels observed in TERM infants LA levels observed in PRETERM infants

Median LA levels present throughout the 3rd trimester

5
0
Martin et al, Journal of Pediatrics, 2011

2 3 Postnatal Week (Birth = Week 0)

Low DHA Levels are Linked to the Development of Chronic Lung Disease (CLD)
7
Mean DHA levels for all infants

Mean DHA level, mol%

*
No CLD 5

+ CLD

3 0
(n=54)

1
(n=63)

2
(n=56)

3
(n=34)

4
(n=35)

Postnatal week (birth = week 0)

Martin et al, Journal of Pediatrics, 2011

Postnatal Alterations in Select Fatty Acids & Ratios are Associated with an Increased Risk of CLD & Late-Onset Sepsis
CLD LA AA DHA LA: DHA Late-onset sepsis LA AA DHA LA: DHA OR (95% CI) 0.9 (0.7, 1.1) 0.9 (0.6, 1.3) 2.5 (1.3, 5.0) 8.6 (1.4, 53.1) Hazard ratio (95% CI) 0.8 (0.7, 0.96) (1.3) 1.4 (1.1, 1.7) 1.4 (1.0, 2.0) 4.6 (1.5, 14.1) p 0.4 0.6 0.001 0.02 p 0.02 0.02 0.08 0.007

Models adjusted for gestational age, gender, growth restriction, severity of illness, total Intralipid intake Martin et al, Journal of Pediatrics, 2011

Postnatal Alterations in Select Fatty Acids Associated with an Increased Risk of CLD & Late-Onset Sepsis
DHA
CLD
Outcomes
Outcomes

AA
CLD

LOS

LOS

ROP 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

ROP 0.0 0.5 1.0 1.5 2.0

Odds Ratio

Odds Ratio

Martin et al, Journal of Pediatrics, 2011

Putting it All Together

8

Current delivery of nutrition fails to maintain DHA levels

Median DHA levels at birth in TERM infants Median DHA levels at birth in PRETERM infants Median DHA levels present throughout the 3rd trimester

Median DHA level, mol% 4 5 6 7

DHA Deficit

Parenteral phase

Enteral phase

1 2 Postnatal Week (Birth = Week 0)

Martin et al, Journal of Pediatrics, 2011

Unique Developmental Needs

Needs of the Premature Infant Unmet

Defining the Needed Changes

Fats

Proteins

Carbohydrates

Postnatal DHA Deficiency Inevitable Consequence of Current Recommendations & Practice in Preterm Infants

GA< 28 weeks, n=40

Autopsy data, n-3 content in skeletal muscle

Lapillonne 2010

Postnatal DHA Deficiency Inevitable Consequence of Current Recommendations & Practice in Preterm Infants

Cumulative DHA deficit

Correlation between birth weight & cumulative DHA deficit

Lapillonne 2010

Early Alterations in Fatty Acids Occur During a Critical Period of Immune & Organ Development

Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center

PPAR is expressed in enterocytes & bronchial epithelial cells

Ileum

Lung
Ollero, et al. J Cellular Physiology 2004;200:235244

Microbiome

Influence the adhesion of Lactobacillus Lactic acid bacteria dominate

PPARs

PPAR=Peroxisome proliferator-activated receptor

Wahli W. Journal of Internal Medicine 2008;263:613-619 Marion-Letellier, et al. Gut 2009;58:586-593

BM & Infant FA Levels Associated With Infant Cognitive Development

Sabel et al Prostaglandins, Leukotrienes and Essential Fatty Acids 2012

Parenteral Phase of Lipid Delivery

Median DHA level, mol% 4 5 6 7

Parenteral phase

Enteral phase

1 2 Postnatal Week (Birth = Week 0)

Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center

Enteral Phase of Lipid Delivery

Median DHA level, mol% 4 5 6 7

Parenteral phase

Enteral phase

1 2 Postnatal Week (Birth = Week 0)

Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center

PUFA Supplementation and Disease in Neonatal Disease Models

NEC
(Rat Model)

Prematurity DHA Low DHA

Preterm Infants
ROP
(Mouse Model)

PUFAs and Necrotizing Enterocolitis

AA+DHA

Egg PL

DHA

Control

Lu et al. Pediatric Research, 2007

Decrease PAFR and TLR4 gene expression

Omega-3 and Retinopathy of Prematurity

Vasoobliteration / Neovascularization:

21.5 / 9

13.7 / 5.7

Connor et al. Nature Medicine, 2007

Mouse pups exposed to 75% O2 from P7 P12

Omega-3 and Retinopathy of Prematurity

21.9 / 8.3 11.9 / 4.3

Connor et al. Nature Medicine, 2007

- 3 PUFA suppresses TNF-

PUFA Supplementation and Disease in Neonatal Disease Models

NEC
(Rat Model)

Prematurity DHA Low DHA

Preterm Infants ROP
(Mouse Model)

LCPUFAs in preterm infants: Cochran Review

Cochrane Neonatal Group. Publication status and date: 2011 Review content assessed as up-to-date: 27 December 2010 Schulzke SM, Patole SK, Simmer K. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD000375. DOI: 10.1002/14651858.CD000375.pub4.Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

On pooling of results, no clear long-term benefits or harms (if growth the only parameter) were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

Mental Development & DHA Supplementation

Randomized, double-blind enteral supplementation < 33 weeks of gestation High DHA (1% total FA) versus standard (0.3% of total FA) Day 2-4 to term Outcome: NDI at 18 months

Makrides JAMA 2009

Enteral phase may be too late

Current delivery of nutrition fails to maintain DHA levels
8
Median DHA levels at birth in TERM infants

Median DHA levels present throughout the 3rd trimester

Median DHA level, mol% 4 5 6 7

Median DHA levels at birth in PRETERM infants

DHA Deficit

Parenteral phase

Enteral phase

3 0

2 3 Postnatal Week (Birth = Week 0)

Delayed Enteral Feeding

% of infants with any enteral feedings
DOL 0 100 90 80 70 60 50 40 30 20 10 0 DOL 3 DOL 5 DOL 7 DOL 14

d14 d7

% infants

d5
d3 d0

23

24

25

26

27

Gestational Age (weeks')

What Dictates Adequate Enteral Replacement of Fatty Acids?

1. 2. 3. 4.

Achieving Adequate Levels Targeting Critical Balance of n3:n6 Fatty Acids Ensuring Effective Digestion Optimizing Absorption

Maldigestion/Malabsorption of DHA Occurs in Premature Infants

Unpublished data
Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center

Lipid Emulsions

Deshpande and Simmer Current Opin in Clin Nutr and Met Care 2011

Omega-6 (linoleic)

Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Alwayn et al., Pediatr Res 2005;57:445-452.
Reversal of parenteral nutritionassociated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Gura KM et al., Pediatrics 2006;118(1):e197-201.

Omega-3 (linolenic)
Innis. NeoReviews. 2002;3(3):e49

2010 Patient population: n=40, BW< 1250g Intervention: Composition/blend of Omegaven & Clinoleic Control group: Historical - Clinoleic

Pawlick Pediatrics 2011

Pawlick Pediatrics 2011

Parenteral Nutrition of Preterm Infants with a Lipid Emulsion Containing 10% Fish Oil: Effect on Plasma Lipids and Long-Chain Polyunsaturated Fatty Acids
2011 Patient population: n=47, BW< 1250g Intervention: Omegaven vs IntraLipid N=23, 10% fish oil (2.3% DHA) v n=24 MCT/soybean oil (trace amounts DHA)

Rita DAscenzo, et al. J Pediatrics 2011

Study group with LOWER AA

Conclusions
Lipids are an important source of energy and aids in gluconeogenesis
Goal: 3 3.5 g/kg/day

LCPUFAs are biomagnified from mother to fetus during the last trimester Fatty acids (FA) are essential for organ growth and regulation of

inflammation
FA profiles are dramatically altered in the early postnatal period Changes in postnatal FA profiles are linked to neonatal disease

New strategies, that include both the parenteral and enteral periods, need

to be developed to maintain birth levels of FA

New strategies need to consider the role and balance of all critical FA

THANK YOU
cmartin1@bidmc.harvard.edu