The effect of prenatal docosahexaenoic acid supplementation onbreast milk fatty acid composition and morbidity and immunefunction in Mexican infants: a double-blind randomized, controlledtrial Open Access

Abstract

Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA) found in high concentrations in brain and retinal cell membranes, accumulates rapidly in neural tissue during later gestation and infancy.DHA is also found in cells of the immune system and modulates immunity and inflammation through mechanisms including modulation of gene expression, alteration of cell membrane structure and function, and subsequent modification of cytokine and eicosanoid profiles and alteration of lipid raft structures. DHA is preferentially transferred across the placenta and is present in breast milk, and availability of DHA to the developing fetus and its concentration in breast milk is primarily dependent upon maternal diet. Pre-formed DHA is found in high concentrations in oily coldwater fish such as salmon and herring, and dietary intake of DHA-rich foods in many populations of pregnant and lactating women is inadequate. Infants are born with immature immune systems and are therefore more susceptible to infectious disease, a leading cause of morbidity and mortality in children the developing world. The substantial impact of nutritional status on infectious disease is well known and is especially important in children.

Given the import role of DHA in child development and immune function, we investigated the effect of DHA in pregnancy on breast milk PUFA concentrations, infant morbidity and infant response to hepatitis B and tetanus vaccination. In a double-blind randomized, controlled trial in Mexico, 1040 pregnant women were supplemented daily with 400 mg algae-derived DHA or placebo from 18-22 weeks' gestation through parturition. We found that DHA supplementation improved breast milk DHA concentration at 1 month post-partum and overall, reduced the duration of illness symptoms in infants. Additionally, infants in the DHA group had lower mean concentrations of anti-hepatitis B IgG antibody at 3 months of age, after vaccination at birth and at 2 months.

Our findings contribute to the mounting evidence that perinatal omega-3 PUFA nutriture, including in utero exposure and exposure through breast milk, may influence the development and maturation of fetal and infant immune response. Additionally, we report novel findings about the influence of DHA in pregnancy alone on breast milk DHA concentrations.

Table of Contents

Table of Contents Chapter 1: Introduction ................................................................................................ 1 Chapter 2: Literature review Overview of n-3 polyunsaturated fatty acids................................................................... 8

Essentiality, structure and metabolism of DHA ..................................................................... 8 Dietary sources and recommended intake of DHA ................................................................ 10 Overview of n-3 PUFA functions ...................................................................................... 12 n-3 PUFAs in pregnancy ................................................................................................. 12 n-3 PUFAs in lactation.................................................................................................... 15 Chapter summary ......................................................................................................... 18 Chapter 3: Literature review Polyunsaturated fatty acids and immune function ....................................................... 19 Overview of infant immune function ............................................................................... 19 LCPUFAs and immune function: mechanisms of action ........................................................ 20 n-3 PUFAs and immune function: trials in animals............................................................... 23 n-3 PUFAs and immune function: trials in adults ................................................................ 26 n-3 PUFAs and immune function: trials in children .............................................................. 29 n-3 PUFAs supplementation in lactation and breast milk immunoglobulins ................................ 31 In utero programming of immune function ........................................................................ 32 Chapter summary ........................................................................................................ 33 Conceptual framework describing the potential relationship between maternal diet in pregnancy and infant immune function ........................................................................... 34 Chapter 4: Methods .................................................................................................. 36 Objectives and hypotheses .......................................................................................... 36 Study setting and population and ethical considerations .................................................... 37 Study design ............................................................................................................. 39 Data collection .......................................................................................................... 40 Laboratory methods ................................................................................................... 41 Recruitment of study subjects and power calculations ...................................................... 46 Power calculations ..................................................................................................... 46 Statistical methods .................................................................................................... 47 Chapter 5: Docosahexaenoic acid supplementation from mid-pregnancy through parturition influenced breast milk fatty acid concentrations at 1 month postpartum in a double-blind randomized, controlled trial in Mexico ............................................... 51 Abstract ................................................................................................................... 54 Introduction .............................................................................................................. 56 Methods.................................................................................................................... 57 Results ..................................................................................................................... 62 Discussion ................................................................................................................. 63 Literature cited .......................................................................................................... 69

Chapter 6: Prenatal docosahexaenoic acid supplementation and infant morbidity: a double-blind randomized, controlled trial in Mexico ........................................................... 77

Abstract .................................................................................................................... 80 Introduction ............................................................................................................... 81 Methods..................................................................................................................... 82 Results ...................................................................................................................... 86 Discussion .................................................................................................................. 90 Literature cited ........................................................................................................... 96 Chapter 7: Prenatal docosahexaenoic acid supplementation and infant response to hepatitis B and tetanus vaccination in a double-blind randomized, controlled trial in Mexico ...................................................................................................................... 108 Abstract ..................................................................................................................... 110 Results ....................................................................................................................... 117 Discussion ................................................................................................................... 118 Literature cited ............................................................................................................ 125 Chapter 8: Summary and conclusions ........................................................................... 132 Key findings ................................................................................................................. 132 Strengths and limitations................................................................................................. 137 Implications of the study findings...................................................................................... 140 Future analyses and studies ............................................................................................ 144 Summary ..................................................................................................................... 145 Literature cited............................................................................................................ 147 Appendices ................................................................................................................. 158 Form 20: Infant feeding practices.......................................................................................162 Form 25: 15 day morbidity recall ....................................................................................... 162

List of figures Figure 1: Docosahexaenoic acid structure...............................................................................9 Figure 2. Metabolism of LCPUFAs..........................................................................................11 Figure 3. Synthesis of eicosanoids from AA and EPA.................................................................22 Figure 4: Conceptual framework describing the potential influence of in utero exposure to DHA on infant immune function..................................................................36 Figure 5: Plate layout for determinations of antibody concentrations...........................................45 Figure 6: Flow chart instructions for Luminex (for determination antibody concentrations)..................................................................................................................46

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition
Keyword	Morbidity Breast milk Prenatal Docosahexaenoic acid DHA Omega-3 fatty acids Immune function Infant
Committee Chair / Thesis Advisor	Ramakrishnan, Usha, Emory University
Committee Members	Martorell, Reynaldo, Emory University Kapasi, Zoher, Emory University Vogt, Robert , Centers for Disease Control and Prevention Stein, Aryeh, Emory University

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