Fatty acid and micronutrient intake and status in association with allergy among pregnant urban women in South Africa

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Fatty acid and micronutrient intake and status in

association with allergy among pregnant urban

women in South Africa

I van Zyl

orcid.org/ 0000-0002-4506-0547

Mini-Dissertation submitted in partial fulfilment of the

requirements for the degree Master of Science in Dietetics at

the North-West University

Supervisor:

Dr L Malan

Co-supervisor:

Prof CM Smuts

Graduation July 2018

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ACKNOWLEDGEMENTS

First and foremost, to my dear Lord Jesus Christ, thank you for enabling and strengthening me to complete this mini-dissertation. I would never have been able to complete this task, without your guidance and grace.

Second, to my loving and supportive husband, Cilliers van Zyl, thank you for being my rock. Without your support and encouragement, I would not have had the perseverance that was required of me. Thank you to my beautiful children; Joshua, Eben and Meah, for your patience and unconditional love. I love you all indescribably.

To my family and friends, thank you for your loving support and prayers throughout this time. Thank you for your encouragement, it sustained me.

To Dr Linda Malan, my supervisor. How can I ever thank you enough? You have been an enormous help and motivator throughout this journey. Thank you for never giving up on me. You have not only been my supervisor, but also my friend. Thank you for understanding when times were tough, and the process was delayed. Thank you for patiently guiding and teaching me.

To Prof Marius Smuts, my co-supervisor, thank you for your unending support and patience. Thank you for your excellent guidance and input throughout this journey. To Elize Symington, the creator of NuPED, thank you for allowing me on your NuPED team. Thank you for always lovingly assisting when I needed help and guidance. Because of you, my dissertation became a reality. Thank you for being a great leader.

To Adriaan Jacobs, Cecile Cooke and Linda Malan at the Centre of Excellence in Nutrition (CEN) laboratory, thank you for your hard work with storage, management and analysis of the samples at the NWU.

To the whole NuPED team, thank you for your great team work. You are all amazing people. A special thank you goes to Mieke Faber, Caylin Goodchild, Cornelia Conradie and Milton Semenekane. Thank you for all your hard work and help on completing the dietary data.

Lastly, I would like to thank all the sponsors of the NuPED study: SA National Research Foundation, South African Sugar Association, South African Medical Research Council, United Kindom Medical Research Council and the Allergy Society of South Africa. Thank you for providing the funding and opportunity to be a part of this study.

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ABSTRACT

Background: Allergy has become a global problem, consequently reaching epidemic proportions. Worldwide, in both developed and developing countries, the prevalence of allergic disease is rising substantially, with an estimated prevalence of 10–30% of the population being affected. Allergic diseases are a major cause of morbidity. In South Africa, data on the prevalence of allergies in adults are scarce. Dietary intake and nutritional status, particularly of fatty acids and certain micronutrients, may affect allergy in adults. This is of importance in pregnant women, since maternal allergy has been shown to affect the allergic status of their infants. The identification of specific nutrient status and/or intake as modifiable risk factors would be of great value for future prevention and treatment strategies in the mother and her offspring.

Aim: To investigate the prevalence of allergy and its association with fatty acid and iron status, as well as zinc and Vitamin E intake, in pregnant urban women in South Africa. Design: This study was nested in the Nutrition during Pregnancy and Early Development (NuPED) study. Within the nested study, associations of maternal dietary intake and nutritional status markers with allergic disease were determined in a cross-sectional manner at <18 weeks of pregnancy. Nutritional status and -intake were compared between the allergic group (n=20) and the non-allergic group (n=82).

Results: Based on the ISAAC questionnaire, 19.6% of pregnant women had self-reported allergy symptoms, consisting of a mixture of rhinitis (70% [n = 14/20]), asthma (30% [n = 6/20]), and eczema (15% [n = 3/20]). Gamma linolenic acid (GLA, P=0.021) and arachidonic acid (AA, P=0.044) were lower in allergic women. The dihomo-gamma-linolenic acid (DGLA) to GLA ratio was higher (P=0.042) and the AA to GLA ratio (P=0.075) tended to be higher in allergic women. Total PUFA (P=0.068) and n-6 LCPUFA (P=0.062) tended to be lower in allergic women. Allergic women showed a trend to have higher trans-vaccenic acid (VA) levels (P=0.089) and lower n-6 PUFA levels (P=0.084). More allergic than non-allergic women showed a trend to have an n-3 PUFA (P=0.082), n-3 LCPUFA (P=0.082), and AA (P=0.082) status below the median of the total study population. More allergic than non-allergic women had a DGLA to GLA ratio (P=0.019) above the median, and more allergic than non-allergic women tended to have an AA to GLA ratio (P=0.066) above the median. There was no difference between iron status markers or iron deficiency prevalence; vitamin E and zinc dietary intake; or inflammatory markers or inflammation prevalence of the allergic and non-allergic women.

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Conclusion:

Our data showed an allergy prevalence of 19.6%. These pregnant urban women in South Africa with allergy symptoms have lower RBC GLA and AA concentrations, and a higher DGLA to GLA ratio, as compared to their non-allergic counterparts. These altered FA concentrations and ratios suggest a novel mechanism of FA in allergy, indicative of the up-regulation of the FA elongation and possibly desaturation metabolism, with stronger evidence towards elongation. Our study could be extended by investigating lipid mediator concentrations in this population.

Key words: allergy / allergic disease; pregnancy; fatty acid composition; iron; vitamin E; zinc

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OPSOMMING

Agtergrond: Allergie is huidiglik 'n wêreld-wye probleem, wat gevolglik epidemiese proporsie bereik het. Wêreldwyd, in beide ontwikkelde en ontwikkelende lande, styg die insidensie van allergiese siektetoestande aansienlik, met 'n geraamde 10-30% van die bevolking wat geaffekteer word. Allergiese siektes is 'n belangrike oorsaak van morbiditeit. In Suid-Afrika is data oor die voorkoms van allergieë by volwassenes skaars. Nutriënt inname en -status, veral van vetsure en sekere mikronutriënte, kan allergieë by volwassenes beïnvloed. Dit is van spesifieke belang by swanger vrouens, aangesien die allergie van ŉ ma, die allergiese toestand van haar baba beïnvloed. Die identifisering van spesifieke nutriënte, as wysigbare risiko-faktore, sal van groot waarde wees vir toekomstige voorkomings- en behandelingstrategieë in die moeder, sowel as in haar nageslag.

Doelwit: Om die insidensie van allergie en die assosiasie daarvan met vetsuur- en ysterstatus, sowel as sink- en vitamien E-inname, in swanger stedelike vrouens in Suid-Afrika te ondersoek.

Ontwerp: Hierdie was ŉ geneste studie in die “Voeding tydens swangerskap en vroeë ontwikkeling” (NuPED) studie. Binne hierdie geneste studie is die assosiasies van nutriënt inname en -status merkers met allergiese siekte met 'n dwarsdeursnit ontwerp tydens <18 weke van swangerskap bepaal. Voedingsstatus en -inname is vergelyk tussen die allergiese groep (n = 20) en die nie-allergiese groep (n = 82).

Resultate: Op grond van die ISAAC-vraelys het 19,6% van die swanger vrouens self-gerapporteerde allergie simptome gehad, bestaande uit 'n mengsel van rinitis (70% [n = 14/20]), asma (30% [n = 6/20]), en ekseem (15% [n = 3/20]). Gamma linoleensuur (GLS, P = 0,021) en aragidoonsuur (AS, P = 0,044) was laer in allergiese vrouens. Die verhouding tussen dihomo-gamma-linoleensuur (DGLS) en GLS was hoër (P = 0,042) en die AS tot GLS verhouding (P = 0,075) was geneig om hoër te wees in allergiese vrouens. Totale poli-onversadigde vetsure POVS (P = 0.068) en n-6 lang-ketting (LK) POVS (P = 0,062) was geneig om laer te wees in allergiese vrouens. Allergiese vrouens het 'n tendens getoon om hoër trans-vakseensuur (VS) vlakke (P = 0,089) en laer n-6 POVS -vlakke (P = 0,084) te hê. Meer allergiese as nie-allergiese vrouens het 'n neiging getoon om 'n n-3 POVS (P = 0.082), n-3 LKPOVS (P = 0.082) en AS (P = 0.082) status onder die mediaan van die totale studie populasie te hê. Meer allergies as nie-allergiese vrouens het 'n DGLS tot GLS-verhouding (P = 0,019) bo die mediaan gehad, en meer allergies as nie-allergiese vrouens was geneig om 'n AS tot GLS-verhouding (P = 0,066) bo die mediaan te hê. Daar was geen verskil tussen ysterstatusmerkers of die insidensie

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van ystertekort nie; asook geen verskil tussen vitamien E en sink dieet inname; of inflammatoriese merkers of die insidensie van inflammasie tussen die allergiese en nie-allergiese vrouens nie.

Gevolgtrekking: Ons data toon 'n allergie-insidensie van 19,6%. Hierdie stedelike swanger vrouens in Suid-Afrika toon laer rooi-bloed sel GLS en AS konsentrasies, sowel as ‘n hoër verhouding tussen DGLS en GLS in vergelyking met die nie-allergiese vrouens. Hierdie gewysigde vetsuur konsentrasies en verhoudings suggereer 'n nuwe meganisme van vetsure in allergie, wat die opregulering van die elongase en moontlik desaturase-paaie impliseer, met sterker bewyse van elongase. Ons studie kan uitgebrei word deur die lipied-mediator konsentrasies in hierdie populasie te ondersoek.

Sleutelterme: allergie / allergiese siektes; vetsuursamestelling; swangerskap; yster; vitamien E; sink

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ABBREVITIONS

AA arachidonic acid

ALLSA the allergy society of South Africa BHR bronchial hyper-responsiveness COX cyclooxygenase

CRP C-reactive protein CYP cytochrome P450 D5D delta-5 desaturase

DBPCFC double-blind placebo-controlled food challenge DGLA dihomo-gamma-linolenic acid

DHA docosahexaenoic acid EPA eicosapentaenoic acid FA fatty acid

FADS fatty acid desaturation FAME fatty acid methyl ester GLA gamma-linolenic acid

HCG human chorionic gonadotrophin HIV human immunodeficiency virus HREC health research ethics committee IFN interferon

ID iron deficiency IgE Immunoglobulin E

ISAAC International Study of Asthma and Allergies in Childhood LA linoleic acid

LCPUFA long-chain polyunsaturated fatty acids LTs leukotrienes

LOX lipoxygenase

MUAC mid-upper arm circumference n-3 omega 3

n-6 omega 6

NCD non-communicable disease PKC protein kinase C

PGs prostaglandins

PUFA polyunsaturated fatty acid

QFFQ quantitative food frequency questionnaire RBC red blood cells

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RMMCH Rahima Moosa Mother and Child Hospital SF serum ferritin

SPT skin prick test TfR transferrin receptor

TGF-β transforming growth factor beta Th T-helper

TXs thromboxanes

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LIST OF TABLES

TABLE 1.1: TEAM MEMBERS AND THEIR ROLES AND EXPERTISE ... 4

TABLE 3.1: SUMMARY OF INCLUSION AND EXCLUSION CRITERIA AT SAMPLING ... 32 TABLE 3.2: SCHEDULE OF STUDY ACTIVITIES. ... 38

TABLE I BASELINE CHARACTERISTICS OF PARTICIPANTS1_{... 47}

TABLE II PERCENTAGE OF ALLERGIC WOMEN WITH ASTHMA,

ECZEMA OR RHINITIS1_{... 48}

TABLE III FATTY ACID STATUS OF ALLERGIC AND NON-ALLERGIC WOMEN1_{... 50}

TABLE IV PERCENTAGE OF ALLERGIC AND NON-ALLERGIC WOMEN WITH N-3 AND N-6 FATTY ACID STATUS BELOW AND ABOVE THE MEDIAN OF THE STUDY POPULATION (N=102)1_{... 51}

TABLE V IRON STATUS OF ALLERGIC AND NON-ALLERGIC WOMEN1

... 52 TABLE VI VITAMIN E AND ZINC DIETARY INTAKE OF ALLERGIC AND

NON-ALLERGIC WOMEN1_{... 52}

TABLE VII INFLAMMATORY MARKERS IN ALLERGIC AND

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LIST OF FIGURES

FIGURE 1 THE N-6 AND N-3 PUFA DESATURATION AND ELONGATION PATHWAYS, AND THE PRODUCTION OF SELECTED LIPID MEDIATORS. HDHA, HYDROXYDOCOSAHEXAENOIC ACID; HEPE, HYDROXYEICOSAPENTAENOIC ACID; HETE,

HYDROXYEICOSATETRAENOIC ACID, PG, PROSTAGLANDIN ... 42

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CHAPTER 1 INTRODUCTION

1.1 Rationale of the Study

Allergy has become a global problem and is currently the most common and earliest-onset non-communicable disease (NCD), consequently reaching epidemic proportions (Prescott, 2013). Approximately 20% of women of childbearing age have allergic diseases (Schatz et al., 2014), of which maternal atopic status is strongly associated with the development of atopic disease in her offspring (Prescott & Allen, 2011). The prevalence of true allergic disease in pregnant urban women in South Africa is currently unknown, as studies performed in South Africa are scarce. Furthermore, of those performed, some used poor diagnostic tools, making it difficult to extrapolate the true prevalence of allergic disease in South Africa (Gray & Kung, 2012).

Nutrient intake and nutritional status, particularly of fatty acids (FA) and anti-oxidative micronutrients, may affect allergy in adults (Calder, 2015; Sala-Vila et al., 2008). A leading hypothesis in relation to nutrition is that the significant increases in prevalence of allergic diseases in Western countries may partially be explained by changes in modern diet, specifically changes in the intake of dietary fats (Gray & Levin, 2014; Klemens et al., 2011; Nwaru et al., 2012; Trak-Fellermeier et al., 2004). Consumption of omega-6 (n-6) poly-unsaturated fatty acids (PUFA) rich foods has increased, whereas that of omega-3 (n-3) PUFA has decreased over the past few decades (Blasbalg et al., 2011; Kremmyda et al., 2011). This change in the dietary fat intake pattern has been suggested to increase the incidence of IgE-mediated allergic diseases (Nwaru et al., 2012).

FA status reflect FA intake (Ford et al., 2016; Tricon et al., 2006). Differences in FA status between allergic and non-allergic subjects have previously been described (Ford et al., 2016; Malan et al., 2016; Manku et al., 1982). Dietary antioxidant intake has also been hypothesised to influence allergic disease (Allan et al., 2010; Seaton et al., 1994). Iron deficiency (ID) has been associated with allergic disease. The main risk factors of iron deficiency, include: a low iron intake; poor absorption of iron from diets high in phenolic compounds or phytate; a period of life when iron requirements are high, such as growth during childhood and pregnancy (WHO, 2008); as well as malabsorption of iron and gastro-intestinal (GIT) iron losses in i.e. allergy (Repetto et al., 1996; Vanderhoof & Kleinman, 2015). Many studies have shown low maternal iron status to be associated with allergy in the offspring (Drury et al., 2016; McEvoy et al., 2014; Oh et al., 2010; Shaheen et al., 2004; Weigert et al., 2015).

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Dietary intake and nutritionalstatus of FA and anti-oxidative micronutrients is particularly important in pregnant women, since maternal allergy has been shown to affect the allergic status of their infants (Gray & Kung, 2012; Patelarou et al., 2011a; Prescott & Allen, 2011). The identification of modifiable risk factors in allergic disease, would be of great value for future prevention and treatment strategies. This study investigates the prevalence of allergy and its association with FA and micronutrient status and intake, in pregnant urban women in South Africa.

1.2 Aim

The aim of this study was to investigate the association between allergic disease and the dietary intake of antioxidative micronutrients and nutritional status of fatty acids and iron, in a mixed population of pregnant women in urban South Africa.

1.3 Objectives

The objectives of the study were, in pregnant women living in urban South Africa,  to determine the prevalence of allergic disease;

 to investigate the association of red blood cell fatty acid- and iron status with allergic disease;

 to investigate the association of the dietary intake of zinc and vitamin E with allergic disease.

1.4 Ethics Approval

Ethics approval for this study has been obtained from the health research ethics committee (HREC) of the Faculty of Health Sciences of the NWU, Potchefstroom (NWU-00186-15-A1-02), as well as from the University of Witwatersrand (M150968). Permission to conduct the study has also been given by the clinical manager of the Rahima Moosa Mother and Child Hospital (RMMCH), as well as by the clinical head of obstetrics and gynaecology at RMMCH. Both the Gauteng Department of Health and the Johannesburg Health District's District Research Committee granted permission to conduct this research study.

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1.5 Research Team

My (Idonette van Zyl’s) specific role as the MSc student included data capturing and quality checks of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires. I partly conducted the dietary coding, quality checks and data cleaning of the Quantitative Food Frequency Questionnaires (QFFQ). I also partly calculated the living standards measure (LSM) score for all the participants. I performed the statistical analyses and writing of the mini-dissertation including the article manuscript under supervision of my study-leaders.

Some of the other members as part of the NuPED team, who are not co-authors of Chapter 4, include: Dr AJ Wise from the University of the Witwatersrand and RMMCH (supervisory gynaecologist); Ms M Bezuidenhout (phlebotomist) and Dr OF Sotunde (post-doctoral fellow).

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Table 1.1: Team members and their roles and expertise

Affiliation Name Role Relevant Expertise Permission Signatures North-West University Mrs Idonette van Zyl MSc student Author Data coding, capturing and quality control

Registered dietician with specific focus on allergies

North-West University

Dr. Linda Malan MSc student supervisor Co-Author Study design

Essential fatty acid and micronutrient nutrition; Role of essential fatty acids and iron in immune development and

functioning; Community-based clinical trials, Laboratory specialist North-West University Prof. Marius Smuts Co-supervisor of MSc student and principal investigator of the main study Co-Author

Essential fatty acid and micronutrient nutrition; Nutrition during

pregnancy and infancy; Community-based clinical trials North-West University Dr. Jeannine Baumgartner Co-Investigator Co-Author Study design

Essential fatty acid and micronutrient nutrition; Role of essential fatty acids and iron in neurodevelopment; Community-based clinical trials

North-West

University Elize Symington PhD student / Study Coordinator Co-Author Design, implementation and execution of study Nutrition during pregnancy North-West University Dr. L Zandberg Planning, scientific input and data collection Co-author on manuscript Molecular Nutrition North-West University Dr. M Rothman Planning, scientific input and data collection Co-author on manuscript Psychomotor development; dietary intake

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1.6 Structure of this Mini-Dissertation

Chapter Two entails the literature review, which defines and describes allergic disease, as well as the association with fatty acids, iron, zinc and vitamin E.

Chapter Three describes the methodology used throughout this study.

Chapter Four is a manuscript with the title “Allergy is associated with altered red blood cell fatty acid composition of pregnant women in urban South Africa”. It was written in accordance to requirements of the Current Allergy and Clinical Immunology (CACI) journal.

Chapter Five entails the conclusion and recommendations. 1.7 References

Allan, K., Kelly, F. & Devereux, G. 2010. Antioxidants and allergic disease: a case of too little or too much? Clinical & Experimental Allergy, 40(3):370-380.

Blasbalg, T.L., Hibbeln, J.R., Ramsden, C.E., Majchrzak, S.F. & Rawlings, R.R. 2011. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. The American journal of clinical nutrition, 93(5):950-962. Calder, P.C. 2015. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta, 1851(4):469-484. Drury, K.E., Schaeffer, M. & Silverberg, J.I. 2016. Association between atopic disease and anemia in US children. The Journal of the American Medical Association

pediatrics, 170(1):29-34.

Ford, R., Faber, M., Kunneke, E. & Smuts, C.M. 2016. Dietary fat intake and red blood cell fatty acid composition of children and women from three different geographical areas in South Africa. Prostaglandins, Leukotrienes and Essential Fatty Acids, 109:13-21.

Gray, C.L. & Levin, M.E., 2014. Epidemiology of food allergy. Current Allergy & Clinical Immunology, 27(3):170-176.

Gray, C.L. & Kung, S. 2012. Food allergy in South Africa: joining the food allergy epidemic? Current Allergy & Clinical Immunology, 25.

Klemens, C.M., Berman, D.R. & Mozurkewich, E.L. 2011. The effect of perinatal omega-3 fatty acid supplementation on inflammatory markers and allergic diseases: a systematic review. An International Journal of Obstetrics & Gynaecology, 118(8):916-925.

Kremmyda, L.-S., Vlachava, M., Noakes, P.S., Diaper, N.D., Miles, E.A. & Calder, P.C. 2011. Atopy risk in infants and children in relation to early exposure to fish, oily fish, or long-chain omega-3 fatty acids: a systematic review. Clinical reviews in allergy & immunology, 41(1):36-66.

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Malan, L., Baumgartner, J., Calder, P.C. & Smuts, C.M. 2016. Low immune cell ARA and high plasma 12-HETE and 17-HDHA in iron-deficient South African school children with allergy. Prostaglandins, Leukotrienes and Essential Fatty Acids, 110:35-41. Manku, M.S., Horrobin, D.F., Morse, N., Kyte, V., Jenkins, K., Wright, S. & Burton, J.L. 1982. Reduced levels of prostaglandin precursors in the blood of atopic patients: defective delta-6-desaturase function as a biochemical basis for atopy. Prostaglandins, Leukotrienes and Medicine, 9(6):615-628.

McEvoy, C.T., Schilling, D., Clay, N., Jackson, K., Go, M.D., Spitale, P…Hollister-Smith, J. 2014. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. The Journal of the American Medical Association, 311(20):2074-2082.

Nwaru, B.I., Erkkola, M., Lumia, M., Kronberg-Kippilä, C., Ahonen, S., Kaila,

M…Veijola, R. 2012. Maternal intake of fatty acids during pregnancy and allergies in the offspring. British Journal of Nutrition, 108(04):720-732.

Oh, S., Chung, J., Kim, M., Kwon, S. & Cho, B. 2010. Antioxidant nutrient intakes and corresponding biomarkers associated with the risk of atopic dermatitis in young

children. European journal of clinical nutrition, 64(3):245.

Patelarou, E., Giourgouli, G., Lykeridou, A., Vrioni, E., Fotos, N., Siamaga,

E…Brokalaki, H. 2011. Association between biomarker-quantified antioxidant status during pregnancy and infancy and allergic disease during early childhood: a systematic review. Nutrition Reviews, 69(11):627-641.

Prescott, S. & Allen, K.J. 2011. Food allergy: riding the second wave of the allergy epidemic. Pediatric Allergy and Immunology, 22(2):155-160.

Prescott, S.L. 2013. Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases. Journal of Allergy and Clinical Immunology, 131(1):23-30.

Repetto, T., Materassi, D., Procopio, E. & Novembre, E. 1996. Cerebral venous thrombosis in a child with iron deficiency anemia caused by food allergy. Medical and surgical pediatrics, 19(2):133-134.

Sala-Vila, A., Miles, E.A. & Calder, P.C. 2008. Fatty acid composition abnormalities in atopic disease: evidence explored and role in the disease process examined. Clinical and Experimental Allergy, 38(9):1432-1450.

Seaton, A., Godden, D.J. & Brown, K. 1994. Increase in asthma: a more toxic environment or a more susceptible population? Thorax, 49(2):171.

Shaheen, S., Newson, R., Henderson, A., Emmett, P., Sherriff, A., Cooke, M. & Team, A.S. 2004. Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema. European Respiratory Journal, 24(2):292-297.

Trak-Fellermeier, M., Brasche, S., Winkler, G., Koletzko, B. & Heinrich, J. 2004. Food and fatty acid intake and atopic disease in adults. European Respiratory Journal, 23(4):575-582.

Tricon, S., Willers, S., Smit, H., Burney, P., Devereux, G., Frew, A…Shaheen, S. 2006. Nutrition and allergic disease. Clinical & Experimental Allergy Reviews, 6(5):117-188.

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Vanderhoof, J.A. & Kleinman, R.E. 2015. Iron Requirements for Infants with Cow Milk Protein Allergy. The Journal of pediatrics, 167(4):S36-S39.

Weigert, R., Dosch, N.C., Bacsik-Campbell, M.E., Guilbert, T.W., Coe, C.L. & Kling, P.J. 2015. Maternal pregnancy weight gain and cord blood iron status are associated with eosinophilia in infancy. Journal of Perinatology, 35(8), p.621.

WHO, see World Health Organization

World Health Organization. 2008. Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia.

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Chapter 2 LITERATURE REVIEW

The following literature review aims to describe allergic disease, as well as its association with dietary intake and nutritional status markers, with specific reference to fatty acid and iron status, as well as vitamin E and zinc intake.

2.1 Prevalence of Allergic Disease

Worldwide, in both developed and developing countries, the prevalence of allergic disease is rising substantially, with an estimated 10–30% of the general population being affected (Pawankar & Canonica, 2013; Ring et al., 2012; Tham EH, 2014; Willemsen, 2016). Epidemiological studies have shown that for the last 50 years, there has been a 300–500% increase in the prevalence of allergic disease in Westernised countries (McFadden et al., 2015). Allergic diseases include certain forms of asthma, rhinitis, atopic dermatitis (AD), conjunctivitis, life-threatening anaphylaxis, food allergies, angioedema, urticaria, eosinophilic disorders, including eosinophilic esophagitis, drug- and insect allergies (Pawankar & Canonica, 2013). Allergies, one of the most common and earliest onset of non-communicable diseases (NCDs), are estimated to affect up to 40% of the population in developed countries (Pawankar, 2014). Allergic diseases occur in approximately 20 to 30% of women of childbearing age, contributing as one of the most common conditions complicating pregnancy (Mazzotta et al., 1999).

In South Africa, data on the prevalence of allergies in adults are scarce, whereas more data are available for children. The third phase of the International Study of Asthma and Allergies in Childhood (ISAAC III) study in South Africa, found an allergic disease prevalence of 18–20% in children aged 13–14 years (Ait‐Khaled et al., 2007). An increase in bronchial hyper responsiveness (BHR), a marker for asthma, was found in 17% of rural and 34.4% of recently urbanised Xhosa children (Steinman et al., 2003). Results from the Global Burden of Asthma report ranked South Africa 25th_{worldwide on the prevalence of}

asthma, also suggesting South Africa to have a high asthma burden of disease (Green et al., 2010).

Worldwide, 240–550 million people may be suffering from food allergy (Pawankar & Canonica, 2013). Large population studies and meta-analyses using food challenges, have shown a wide variation in food allergy prevalence, ranging from 1% to over 10%, depending on the age of the child and the region studied (Gray & Levin, 2014). Food allergy has been estimated to affect nearly 5% of adults and 8% of children, with growing evidence of an increase in prevalence (Sampson et al., 2014; Sicherer & Sampson, 2014). The prevalence of food allergy in South Africa is scarce but being studied.

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Currently, no data are available on the prevalence of food-allergy of Black, Coloured, or Caucasian South African adults (Gray & Kung, 2012; Gray & Levin, 2014).

An expert panel sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) defines food allergy as ‘‘an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food’’ (Chafen et al., 2010; Sicherer & Sampson, 2014). Recent studies provided evidence that non-caucasian populations living in more developed environments may even be at greater risk of food allergy (Prescott & Allen, 2011). Indigenous black populations in South Africa have rapidly been urbanising and taking on a westernised diet and lifestyle. Black South Africans have previously been thought to be protected from the food allergy epidemic. However, a recent food allergy prevalence study in eczematous patients in Cape Town has shown a significantly high rate of 42% of challenge-proven food allergies in Xhosa and mixed population group children (Gray & Kung, 2012). These findings suggest that South Africa may in fact not be spared from the rise in the food allergy epidemic. Allergic disease can be expressed in many different organs of the body and in any age group, thereby significantly impacting on the quality of life of these patients and of their families. Currently, the health care of allergic patients, even in developed countries, is far from ideal(Pawankar & Canonica, 2013; Ring et al., 2012; Tanno et al., 2014).

2.2 Allergy Aetiology

Allergy is a hypersensitivity reaction initiated by specific immunologic mechanisms (Johansson et al., 2004). Allergy can be antibody-mediated or cell-mediated. These antibodies mostly belong to the immunoglobulin E (IgE) isotype, and these patients have an IgE-mediated allergy, referring to IgE antibodies to an allergen (Johansson et al., 2004). An allergen is defined as an antigen causing allergic disease (Johansson et al., 2004). In an allergic individual, allergen exposure leads to a process of sensitisation, followed by inflammation seen in many organs (Green et al., 2010). Atopy refers to a personal and/or familial tendency, usually in childhood or adolescence, to become sensitised and to produce IgE antibodies in response to ordinary exposures to potential allergens. These individuals may develop typical symptoms of asthma, rhinitis, or eczema (Johansson et al., 2004). The term atopy may therefore be used to describe the genetic predisposition to becoming IgE-sensitised to potential allergens commonly occurring in the environment, referred to as IgE-antibody high-responders. The term atopy can only be used to describe the condition once an IgE sensitization has been documented by IgE antibodies in serum or by a positive skin prick test (Johansson et al., 2004).

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Allergic diseases are a major cause of morbidity (Rueter et al., 2015). Allergy may cause severe signs and symptoms, including urticaria, angio-oedema, and anaphylaxis. Allergy symptoms such as urticaria may impact significantly on quality of life; reducing sleep, restricting normal daily activities, causing emotional stress and social isolation (Green et al., 2010). IgE-mediated urticaria and angio-oedema may be caused by many triggers such as food, animal dander, medications, insect venom and latex. Severe reactions might progress or be part of the spectrum of anaphylaxis (Green et al., 2010). Anaphylaxis is a serious reaction of rapid onset, which may cause death. It is a syndrome with varied mechanisms, clinical presentation, and severity; resulting from sudden release of inflammatory mediators from mast cells and basophils (IgE- or non-IgE-mediated) (Green et al., 2010). The most common triggers for anaphylactic reactions include food, followed by drugs, latex and insect stings, and idiopathic anaphylaxis (anaphylaxis of unknown cause) (Lieberman, 2014). Anaphylaxis may occur in all age groups, but it is more frequently seen in adults. It is the most catastrophic consequence of all allergic disorders; a medical emergency requiring prompt recognition of symptoms and immediate medical care (Green et al., 2010). Therefore, the identification of these risk factors, as well as possible prevention strategies of allergy, could be of great benefit to human health (Pawankar, 2014; Rueter et al., 2015).

Environmental factors have been ascribed as a strong contributor to the increased prevalence of allergic disease (Netting et al., 2014). Furthermore, several environmental factors have been found to interfere with immune system maturation, to promote immune system dysfunction, and to facilitate allergic disease development (Patelarou et al., 2011a). Potential risk factors for allergic disease based on population-based epidemiological studies include genetics, associated atopic disease (such as atopic dermatitis [AD] being a major risk factor for food allergy), gender (more predominant in males), route of exposure, timing of the ingestion of allergen, antacid medication in infants, increased hygiene, geographical location (may affect patterns of allergen exposure and thus allergy rates), obesity and ethnicity (recent studies have suggested that non-whites may be at greater risk of allergy, especially if they are living in a westernised environment). Another very important environmental factor that is associated with allergy, is diet. Examples of dietary allergy-associated risk factors are reduced consumption of omega 3 (n-3) polyunsaturated fatty acids (PUFA), reduced consumption of antioxidants and other micronutrient and vitamin imbalances. Further investigation is required to clarify the role of these modifiable environmental factors influencing the increase of allergic disease (Gray & Levin, 2014; Sicherer & Sampson, 2014; Willemsen, 2016). Furthermore, maternal dietary intake and nutritional status not only influence their

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own allergy status, but also their offspring’s (Patelarou et al., 2011; Sicherer & Sampson, 2014).

Many potentially modifiable risk factors are inter-related and influenced by changes in behaviour, lifestyle and dietary patterns (Rueter et al., 2015). Some of these risk factors might be proven as effective to prevent or treat allergic disease in both the mother and her offspring (Gray & Levin, 2014; Patelarou et al., 2011; Sicherer & Sampson, 2014). Evidence from animal studies has confirmed that gene expression and disease predisposition by epigenetic mechanisms can be altered through environmental exposures during critical stages of development (Prescott & Allen, 2011). Epigenetics have been described as the bridge between genotype and phenotype. Manifestation of allergy is therefore the result of the change in environment and lifestyle, including diet, possibly affecting genotype expression (Gray & Kung, 2012; Gray & Levin, 2014; Prescott & Allen, 2011). However, even though diet may partially have its association with allergy through epigenetic mechanisms, this mechanism falls outside the scope of this study. A pregnant woman’s allergic and nutritional status has been found to affect allergy development in her offspring (Gray & Levin, 2014; Patelarou et al., 2011; Prescott & Allen, 2011; Sicherer & Sampson, 2014). Therefore, modulating some of the risk factors (such as diet) for allergy, particularly in pregnant women, might be effective to prevent or treat allergic disease in both the mother and her offspring.

2.3 Allergy Diagnosis

Multiple tests have been developed to detect various elements of allergic pathophysiology. However, a thorough clinical history and physical examination should always accompany the interpretation of test results (Van Rooyen, 2014). Currently, available tests have been developed for the detection of both IgE-mediated (immediate) and non IgE-mediated allergy (delayed). IgE mediated tests may include total IgE, allergen specific-IgE, skin prick tests (SPT) and allergen component specific-IgE tests. Most inhalant allergies are IgE-mediated, whereas approximately 50-60% of food allergies are IgE-mediated. Non IgE-mediated allergy tests may include cellular antigen stimulation test (CAST), T-cell mediated tests such as memory lymphocyte immunostimulation assay (MELISA) and skin patch testing (Lloyd, 2015; Van Rooyen, 2014).

Most allergy blood tests and SPT can, however, only indicate allergic sensitization, which should be confirmed with a clinical history and/or an oral challenge test in the case of

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food allergy. Due to its limitations, total IgE is not recommended as a diagnostic tool in allergic disease. Both allergic- and non-allergic conditions may elevate IgE concentrations, e.g. parasitic infestation. Approximately half of IgE-mediated allergic patients might have a total IgE within the normal range. IgE has a limited predictive value in allergy diagnosis (Van Rooyen, 2014).

SPT are used to identify immediate IgE-mediated allergic reactions or allergen sensitisation against specific allergens by measuring the histamine response to an allergen. SPT is an extremely safe procedure according to the Royal College of Pathologists (UK) and the American Academy of Asthma, Allergy and Immunology. SPT is also reliable, easy to perform, give rapid results and are cost-effective (Green et al., 2010). SPTs with allergen extracts are the preferred method of in vivo testing for IgE-mediated sensitivity. Testing for a selected number of common allergens may confirm or exclude atopy. Reliable results are dependent on the quality of the extracts used (Hawarden, 2014). With experience and a thorough allergy history, most well-trained allergists will be able to give a fairly accurate predictive diagnosis after assessing the SPT results together with the clinical history (Morris, 2006). Although in vitro tests and SPT for food allergy are available, the golden standard for the diagnosis of food allergy remains the double-blind placebo-controlled food challenge (DBPCFC). Food challenge testing for food allergy falls outside the scope of this study. SPT should neither be performed during pregnancy, nor in patients with a convincing history of anaphylaxis to the test allergens, due to the small, but possible risk of anaphylaxis.

Although allergy symptoms are diverse, there is consensus that the presence of either eczema, asthma or rhinitis, as used in the international study of asthma and allergies in childhood (ISAAC) indicates that allergic disease is present (Aher et al., 2006). The ISAAC questionnaire has been shown to have good reproducibility and adequate validity, with an ability to distinguish between non-asthmatic and asthmatic patients (Valle et al., 2012). The ISAAC questions on rhinitis are also highly specific and therefore useful in excluding allergic disease. In addition, the ISAAC questionnaire has a high positive predictive value in detecting allergic disease among children with symptoms (Braun-Fahrländer et al., 1997). The ISAAC questionnaire is also useful in assessing childhood asthma due to its criterion validity, inner consistency and external concordance (Fernandez et al., 2005). The ISAAC questionnaire may also be used in adults (Levin, M. 2015. ISAAC in adults [personal correspondence]).

Improved and new methodologies are under development to identify the presence of allergic disease, as well as in determining the severity of allergy and the likelihood of resolution (Van Rooyen, 2014).

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2.4 Allergy in Pregnancy and its Significance

T helper cells (Th) type 2, among others, are associated with the development of allergic disease, whereas Th1 cells antagonise the development of allergic disease (McFadden et al., 2015). Pregnancy is associated with a natural, developmentally programmed skewing of the immune system towards a Th2 bias, persisting for a few months of the neonate’s life, with the purpose of protecting the foetus against rejection by the mother’s immune system (McFadden et al., 2015). Th2 immunity is promoted by oestradiol, progesterone, human chorionic gonadotrophin (HCG), leukaemic inhibitory factor, and prostaglandin D2. There is convincing evidence that increased duration and/or degree of Th2 skewing in pregnancy and early life may be associated with the development of allergic disease in the offspring (Klemens et al., 2011; McFadden et al., 2015). Both HCG and progesterone levels are consistently higher in primigravid women, suggesting an increased Th2 bias during the first pregnancy (McFadden et al., 2015). Independent studies have also found significantly higher IgE cord blood levels in the first pregnancy, indicating a Th 2 bias during that time (McFadden et al., 2015).

Asthma, urticaria, angioedema, eczema, and allergic rhinitis may occur during pregnancy (Schatz & Zeiger, 1997). Approximately 20% of women of childbearing age have allergic diseases, with substantial nasal symptoms occurring in approximately 30% of pregnant women (Schatz et al., 2014), indicating rhinitis to be reasonably common during pregnancy (Namazy & Schatz, 2014; Schatz & Zeiger, 1997). Allergic rhinitis affects approximately 20-40% of women of childbearing age, with 10–30% of these patients experiencing exacerbation of these symptoms during pregnancy (Incaudo & Takach, 2006). Allergic rhinitis is usually pre-existing, although it can develop or be recognized for the first time during pregnancy (Namazy & Schatz, 2016).

The diagnosis of allergic rhinitis refers to episodic symptoms of sneezing, nasal obstruction, rhinorrhoea, and conjunctival-, nasal- and pharyngeal itching – all occurring upon allergen exposure. Allergic rhinitis generally affects atopic individuals (Mazzotta et al., 1999). While nasal congestion may be the sole symptom of pregnancy rhinitis, nasal pruritus, watery rhinorrhoea and sneezing may also be present. Some general triggers for allergic rhinitis include pollens, house dust mites, moulds, and animal dander (Namazy & Schatz, 2014). As with asthma, pre-existing symptoms of chronic rhinitis may improve, worsen or remain unchanged during pregnancy (Mazzotta et al., 1999; Schatz & Zeiger, 1997).

It has, however, been demonstrated that pregnancy-related hormonal changes can also lead to nasal mucosal congestion secondary to an increase in blood volume, thereby

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increasing nasal mucosal cell activity, resulting in nasal mucosal swelling and increased secretions (Mazzotta et al., 1999; Sorri et al., 1980). Pregnancy rhinitis is defined as nasal congestion in the last six or more weeks of pregnancy without other signs of respiratory tract infection and with no known allergic cause and disappearing completely within two weeks after delivery (Namazy & Schatz, 2014).

A mother’s atopic status is strongly associated with the development of atopic disease in her offspring (Prescott & Allen, 2011). The risk of allergic disease is about 33% if one first-degree relative such as a parent or sibling is allergic and 70% if both parents have atopy (Netting et al., 2014). Both IgE- and non-IgE mediated allergies often present in early life (Miles & Calder, 2015). Although both maternal and paternal atopy is associated with atopic disease in the offspring, maternal influence appears to be the stronger predictor (Cook-Mills, 2015; McFadden et al., 2015; Prescott & Allen, 2011). Few studies have been published, but it appears that allergic women are more likely to have infants with food allergy (Prescott & Allen, 2011). A recent birth cohort study showed that food allergy [positive food skin prick test (SPT) and history of IgE-mediated symptoms] occurred in 13% of one-year-old infants of atopic (SPT+) women, compared with only 4% of infants of non-atopic (SPT-) women (Prescott & Allen, 2011). Increasing maternal allergy may therefore be increasing the allergic burden in generations ahead (Gray & Kung, 2012). Atopic predisposition has been described to arise with an innate tendency of the infant, to produce IgE antibodies, which will then lead to the progression of allergic disease in some (Netting et al., 2014).

There is sufficient evidence that a Th2 bias not only affects the presence of atopic disease, but also disease severity (McFadden et al., 2015). The presence of atopic disease in pregnant women and disease severity has been associated with the development of atopic dermatitis and rhinitis in their offspring (Illi et al., 2014). A stronger Th2 bias during pregnancy has been found to be associated with childhood wheezing and atopy at 3 years of age (Kim et al., 2008). Among pregnant women with rhinitis and positive SPT, signiﬁcant increases of Th2 cells in the cord blood of their newborn infants have been found, as well as significantly decreased regulatory T cell (Treg)/Th2 ratios in cord blood (Fu et al., 2013). Children with both a reduced cord blood Th1/Th2 ratio and reduced Treg/Th2 ratio have been shown to display an increased risk of developing atopic dermatitis by the age of two years (Fu et al., 2013). Chang et al., (2004) have also reported the association of atopic dermatitis at six months with elevated total IgE concentrations in cord blood at birth (Chang et al., 2004).

C-reactive protein (CRP) has been associated with allergic conditions such as asthma, urticaria and atopic dermatitis (Deraz et al., 2012; Kasperska‐Zajac et al., 2011). A

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pro-inflammatory status in the mother might predispose the offspring to atopic dermatitis. As such, an increase in maternal and cord blood CRP concentrations has also been associated with a higher risk of eczema, wheezing, and lower respiratory tract infections in early life (Cook-Mills, 2015).

2.5 Allergy and Nutrition

Nutrition has been associated with allergy (Gray & Levin, 2014; Sicherer & Sampson, 2014b; Willemsen, 2016). Dietary-associated risk factors for allergic disease are i.e. reduced consumption of n-3 PUFA, reduced consumption of antioxidants, as well as other micronutrient and vitamin imbalances. More research in this field is required to clarify the role of these modifiable environmental factors on the increase of allergies (Gray & Levin, 2014; Sicherer & Sampson, 2014; Willemsen, 2016). This part of the literature overview will only focus on fatty acids, iron, zinc and vitamin E.

2.5.1 Fatty acids

A leading hypothesis in relation to nutrition is that the significant increases in prevalence of allergic diseases in more developed countries could be partly ascribed to changes in the modern diet, specifically changes in the intake of dietary fats (Gray & Levin, 2014; Klemens et al., 2011; Nwaru et al., 2012; Trak-Fellermeier et al., 2004). Over the past few decades, consumption of n-6 PUFA rich foods has increased, whereas that of n-3 PUFA has decreased. Changes in the type of fatty acid consumption may shift the T-helper balance from type 1 to type 2, which may thereby increase the incidence of IgE-mediated allergic diseases (Nwaru et al., 2012).

PUFAs create a favourable environment for membrane protein function, maintaining membrane fluidity and cell signaling regulation, gene expression and cellular function. Immune cell functioning can be influenced by these PUFA-driven mechanisms. This affects the development and manifestations of atopy. Immune cells typically contain high proportions of n-6 PUFAs. An important link between PUFAs and immunological processes related to atopy is that of the eicosanoid family of immune mediators. The metabolic actions of fatty acids are exerted through these oxygenated metabolites, collectively called eicosanoids or lipid mediators (Bandeira-Melo et al., 2002). These are derived from 20-carbon PUFAs of which Arachidonic acid (AA), an n-6 long-chain (LC)PUFA, is the major substrate (Kremmyda et al., 2011). Eicosanoids, which include prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and other oxidised derivatives, are generated mostly from AA through cyclooxygenase (COX) and lipoxygenase (LOX) enzymes (Kremmyda et al., 2011). Lipid mediators are involved in

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modulating the intensity and duration of inflammatory responses (Kremmyda et al., 2011). Inflammatory lipid mediators, including LTs and PGs play significant roles in the pathogenesis of asthma and other forms of allergic inflammation (Bandeira-Melo et al., 2002).

Eosinophils, one of the key cell types recruited and activated during allergic inflammation, generate eicosanoid derivatives of AA by means of cyclooxygenase and the 5- and 15-lipoxygenase (LO) pathways (Bandeira-Melo et al., 2002). All cutaneous and immune cell types, as well as most other cells, produce eicosanoids that contribute to homeostatic processes and inflammatory responses associated with injury, allergy and other acute or chronic illnesses. Membrane phospholipid-esterified n-6 LCPUFA, mostly AA, are mobilised by phospholipases and serve as precursors to various eicosanoids that are formed by COX, LOX and cytochrome P450 (CYP) enzymes (Nicolaou, 2013).

N-3 PUFA, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can give rise to analogous anti-inflammatory lipid mediators such as resolvins and protectins (Fredman & Serhan, 2011; Nicolaou, 2013). In a recent study in black rural South African children aged 6–11 years, low AA and high 12-HETE (AA-derived pro-inflammatory lipid mediator), but also 17-HDHA concentrations (a DHA-derived anti-inflammatory lipid mediator and precursor of the D-series resolvins) were associated positively with allergy. It was also found that fatty acid composition indicative of impaired delta-5 desaturase (D5D) activity was associated with allergy (Malan et al., 2016). The authors concluded that allergy was associated with production of pro-inflammatory lipid mediators, which consequently triggered the production of n-3 PUFA derived anti-inflammatory lipid mediators to try and resolve inflammation and restore homeostasis (Malan et al., 2016). Others have also found genetic variances in those genes that are involved in fatty acid desaturation (FADS) and/or elongation (ELOVL) possibly resulting in decreased n-3 PUFA status and an allergic phenotype (Ferreria et al., 2005; Lattka et al., 2009). Whilst AA is a precursor for pro-inflammatory eicosanoids, EPA and DHA are precursors for anti-inflammatory eicosanoids (McFadden et al., 2015). Abnormalities have been found in the proportions of the n-3 LCPUFAs in atopic disease. For example, the proportions of EPA and DHA were lower in umbilical cord serum phospholipids from allergic compared with non-allergic mothers (Yu et al., 1996), and lower proportions of DHA and total n-3 PUFA in serum phospholipids have been found in 12- to 15-year-old children with asthma and/or atopic dermatitis compared with age-matched, non-atopic controls (Yu & Björkstén, 1998). Some epidemiological evidence also exists in support of the protective role of n-3 LCPUFA in allergic disease. Greenland Eskimos, of whom most have a high intake of fish and marine mammal oils, seldom have asthma (Kromann &

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Green, 1980). According to the 1st and 2nd National Health and Nutrition Examination Survey (NHANES) in the USA, dietary fish intake has also been found to be protective against wheezing (Schwartz & Weiss, 1990).

It has been hypothesised that maternal diet may impact neonatal immune development with subsequent modification in allergic responses of neonates, such as early IgE sensitisation, presumably being related to maternal diet during pregnancy (Klemens et al., 2011; Nwaru et al., 2010). There is evidence that the inclusion of fish in the maternal diet during pregnancy and/or lactation has a protective effect against the development of atopic disease in their offspring (Miles & Calder, 2015; Schafer et al., 2014). Fish and fish oils are sources of n−3 LCPUFAs; these fatty acids act to oppose the proinflammatory actions of n−6 PUFAs (Kremmyda et al., 2011). When oily fish or fish oil is consumed during pregnancy, foetal n-3 PUFA status (EPA and DHA concentrations) in neonatal plasma, erythrocyte and blood mononuclear cells increases (Miles & Calder, 2015). A study conducted by Furuhjelm et al. (2011) found that high DHA and EPA proportions and low AA/EPA ratios in maternal and infant plasma phospholipids were associated with low incidence of IgE-associated disease in the infants (Furuhjelm et al., 2011). Due to the known biological activities of n-3 LCPUFA, it has been hypothesised that supplementation of n-3 LCPUFA during pregnancy and lactation may serve as a method of primary prevention of allergic diseases in childhood (Klemens et al., 2011). It has been suggested by some interventional studies that n-3 LCPUFA or fish oil supplementation during pregnancy might stimulate immunological changes, which is transferred to the foetus, leading to beneficial effects on allergic disease within the child’s first few years of life (Magnusson et al., 2013). Although not preventing the development of clinical disease, n-3 PUFA supplementation may be beneficial by preventing allergic sensitisation. Supplementation with n-3 PUFA during pregnancy could potentially decrease the growing occurrence of IgE-mediated disease up to two years of life, in which these effects seem to be related to maternal and infant n-3 PUFA plasma proportions in a dose-dependent manner (Furuhjelm et al., 2011).

The current UK recommendations for pregnant and lactating women in terms of n-3 PUFA intake is to consume 1–2 portions (~140 g each) of fish per week, of which at least one should be fatty fish (Miles & Calder, 2015). Safe fatty fish low in methyl mercury include fresh tuna, pilchards, mackerel, sardines, herring, salmon and herring. The aim is to provide a combined amount of EPA and DHA of approximately 450 mg daily. The European Food Safety Authority has recommended an intake of 100–200 mg/day DHA in addition to the recommendation of 250 mg EPA for healthy adults (Miles & Calder, 2015).

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There are several proposed mechanisms whereby n-3 PUFA exerts its anti-allergic actions. Interleukin-13 (IL-13) is also possibly related to allergic disease through inducing IgE synthesis in B cells, and Th2 type differentiation in T cells. Suppression of IL-13 production is a proposed mechanism whereby omega-3 LCPUFA may alter the T-helper cell balance (Klemens et al., 2011). Recent studies have shown that cord blood plasma IL-13 concentrations and messenger RNA coding for IL-4 and IL-13 were reduced in cord blood immune cells in neonates of mothers supplemented with n-3 PUFA during pregnancy (Miles & Calder, 2015). A study conducted by Klemens et al. (2001) found that maternal n-3 PUFA supplementation during pregnancy significantly reduced childhood asthma, as well as the prevalence of positive egg SPT in infants up to 12 months of age. It has also been found that foetal IL-13 production was significantly reduced (Klemens et al., 2011). A study conducted by Palmer et al. (2012) had similar findings with atopic eczema and egg sensitisation being lower in the PUFA supplemental group, although supplementation did not reduce the overall incidence of IgE-associated allergies within the first year of life (Palmer et al., 2012).

Interferon gamma (IFN-γ) has also been associated with multiple auto-inflammatory and autoimmune diseases. In contrast to others, the study by Klemens et al. (2011) found prenatal n-3 PUFA supplementation to neither influence childhood atopic dermatitis, nor alter IFN-γ. However, in children whose mothers received prenatal n-3 PUFA supplementation, there was a non-significant trend towards reduction in clinical food allergy (Klemens et al., 2011).

Transforming growth factor beta (TGF-β) plays a role in allergen tolerance induction via T-regulatory cells and maintenance of low-affinity T- and B-cell secretory IgA production. Studies have also shown an increase in messenger RNA coding for TGF-β in n-3 PUFA supplemented groups (Miles & Calder, 2015). T-cell protein kinase C (PKC) zeta is a kinase isoform inversely associated with the increased risk of atopic dermatitis development and atopic sensitisation (Miles & Calder, 2015). A study by Dunstan et al. (2003) reported significantly higher concentrations of (PKC) zeta in cord blood cells from babies whose mothers were supplemented with n-3 PUFA (Dunstan et al., 2003). However, long-term follow-up is required to establish any effects of n-3 PUFA supplementation on respiratory allergies and aeroallergen sensitisation in childhood (Palmer et al., 2012).

There is some evidence that dietary intake of trans-fatty acids is associated with asthma and atopy (Welland et al., 1999). The International Study of Asthma and Allergies in Childhood (ISAAC) studied the prevalence of asthma, allergic rhino-conjunctivitis, and atopic eczema in children aged 13-14 years, in 155 centres around the world. Prevalence

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estimates were available for 55 study centres in ten countries with data on fatty acid intake. The association between the 12-month prevalence of symptoms of asthma, allergic rhino-conjunctivitis, and atopic eczema and the intake of FAs was established. A positive association between the intake of trans fatty acid intake and the prevalence of symptoms of asthma, allergic rhino-conjunctivitis, and atopic eczema was identified. Tendencies towards stronger associations were found when analyses were restricted to estimates of trans fatty acid intake from mainly hydrogenated vegetable fat sources such as chips, biscuits, oils, and cakes (Welland et al., 1999).

Studies have also found trans fatty acids to influence desaturation, e.g. impaired desaturase activity, as well as chain elongation of n-6 and n-3 PUFA into precursors of inflammatory mediators, such as leukotrienes and prostaglandins. These effects may be stronger for trans fatty acids from hydrogenated vegetable fat than from animal fat(Precht & Molkentin, 1995).

2.5.2 Iron

Iron deficiency (ID) has also been associated with allergic disease. ID is the leading single nutrient deficiency in the world (WHO, 2001). The World Health Organization (WHO) considers it a public health condition of epidemic proportions with significant consequences, including general ill health (WHO, 2001). ID is the most common cause of anaemia during pregnancy, which has led to the WHO recommendation of prenatal use of iron supplements in low- and middle-income countries, as well as in many high-income countries (WHO, 2001). ID involves an insufficient supply of iron to body cells, following depletion of the body’s iron stores. Some of the main contributing factors in ID include an increased requirement for iron (e.g. during pregnancy) with insufficient intake to supply need, a diet poor in absorbable iron, iron losses due to parasitic infections (e.g. hookworm), and other blood losses (Crompton & Nesheim, 2002).

Allergic disorders of the gastrointestinal tract (GIT) may be associated with malabsorption and loss of protein and iron from the GIT (Repetto et al., 1996; Vanderhoof & Kleinman, 2015). A lower iron-status has consistently and reproducibly been found in multiple US cohorts, which clearly associates atopy with anaemia (Drury et al., 2016). Poor foetal iron status; reflecting maternal iron stores, has been hypothesised to be a risk factor in the development of allergy (Weigert et al., 2015). A study conducted in the Pacific Northwest, showed a greatly reduced incidence of asthma and wheezing in infants of mothers who were supplemented with Vitamin C (a known contributor of increased iron bioavailability) during pregnancy (McEvoy et al., 2014). A study conducted in Scottish children, found reduced maternal iron status during pregnancy to be adversely associated with childhood

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wheezing, altered lung function and atopic sensitisation in the first 10 years of life (Nwaru et al., 2014). Also, in the population-based Avon Longitudinal Study of Parents and Children, high iron concentration in umbilical cord samples was associated with a decreased risk of wheezing and eczema in the children (Shaheen et al., 2004).

Most studies however, focus on maternal iron status and the association of allergic disease in the offspring (Drury et al., 2016; McEvoy et al., 2014; Shaheen et al., 2004; Weigert et al., 2015).

2.5.3 Dietary antioxidants

Dietary antioxidants have also gained interest in the field of allergies. Their potential therapeutic- and preventative role in allergic disease, is of specific interest (Allan et al., 2010).

Controversies exist regarding the possible role, if any, of dietary antioxidants in allergic disease. Some have hypothesised the recent increase in allergic disease, specifically asthma, to result from a decline in dietary antioxidant intake in especially westernised countries. This decline in antioxidant intake has been proposed to result from changes in dietary habit, methods of cultivation, and increased transportation, storage and processing of food (Seaton et al., 1994). Others have hypothesised the increase in allergic disease to result from an increase in antioxidant intake due to the increased availability of functional and antioxidant-enriched foods (Allan et al., 2010).

Dietary trends are conflicting; whilst the intake of some antioxidants has declined, the intake of others is likely to have increased. Data on the role of antioxidants in allergic disease from human studies are unclear. Observational epidemiological studies conducted in humans are influenced by several methodological limitations associated with dietary assessment, as well as predominantly focussing on asthma. Potential beneficial associations between dietary antioxidants and allergic outcomes have been reported by most observational studies. However, a small minority have reported potentially adverse associations (Tricon et al., 2006). Several recent studies have emphasised adequate antioxidant intake to be strongly associated with immune maturation. The majority of these published studies have found antioxidant intakes during pregnancy to influence foetal immune programming and allergic disease risk (Patelarou et al., 2011; West et al., 2012). A systematic review conducted by Patelarou et al. (2011) found the larger body of evidence to reveal an inverse associated between maternal antioxidant status during pregnancy, as well as antioxidant intake of a child during the ﬁrst year of life, and allergic disease development during childhood. As part of the review,

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the impact of antioxidants on allergy has been found most evident for antioxidant vitamins, β-carotene, zinc, and selenium (Patelarou et al., 2011).

A number of studies have shown the Mediterranean diet to be rich in antioxidants. This in turn has been associated with a reduced likelihood of asthma, wheezing, and allergic rhinitis (Patelarou et al., 2011). Reduced antioxidant intake during pregnancy has been reported to be negatively associated with atopic dermatitis development in children (Patelarou et al., 2011). Furthermore, a limited number of birth cohort studies have suggested beneficial associations between higher maternal intakes of antioxidants such as vitamin E and zinc and the development of early childhood wheeze, and asthma (Patelarou et al., 2011; West et al., 2012).

2.5.3.1 Zinc

Zinc (Zn) is an essential trace element with a minor plasma pool and rapid turnover. Because zinc has no specialized Zn storage in the body, daily intake is required to support all its functions. It plays a role in DNA synthesis, cellular respiration (carbonic anhydrase), cell division, immune functions, protein synthesis, and wound healing. Zn deficiency is associated with immune system dysfunction and increased inflammation, which might lead to chronic inflammation (Bonaventura et al., 2015).

Zn concentrations have been reported to decrease during stress situations due to pro-inflammatory cytokines such as IL-6 and TNF-α binding Zn ions and releasing them afterwards. Th1 cytokines (IFN-γ, IL-2 and TNF-α) are reduced with Zn deficiency, while the Th2 branch (IL-4, IL-6 and IL-10) is either not affected or is enhanced with Zn deficiency (Diesner et al., 2011; Gordon, 2011).

Insufficient Zin levels interfere with the immune system’s proliferating capabilities, impairing its function and enhancing the risk of developing allergies, auto-immune disorders and infectious diseases (Rosenkranz et al., 2017). Zn particularly influences T-cell development, -differentiation and -activation (Rosenkranz et al., 2017).

Most studies conducted focused on the effect of maternal zinc and offspring outcomes (Nurmatov et al., 2011; Patelarou et al., 2011b). In a systematic review and meta-analysis conducted by Nurmatov et al. (2011), the body of evidence from these studies was found to be methodologically weak, with weak suggestion of the possible effectiveness of zinc in relation to the prevention of asthma (Nurmatov et al., 2011). However, Devereux et al. (2006) suggested a negative association between maternal zinc intake during pregnancy, and ever developing eczema as well as current treatment for eczema at five years of age

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(P value of 0.03 and 0.04, respectively). Overall, Oh et al. (2010) reported a negative association between atopic dermatitis and antioxidant-related nutrient intakes.

The Recommended Dietary Allowance (RDA) is the average daily dietary intake amount, sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals in a particular life-stage group. The current RDA for zinc during pregnancy, in women 19 years and older, is 11 mg/day (Greger, 2001).

2.5.3.2 Vitamin E

Tocopherol isoforms may also influence the development of allergic disease (Cook-Mills, 2015). Vitamin E includes eight natural isomers, of which α-tocopherol and ϒ-tocopherol are two of the most abundant forms. It has been described that ϒ-tocopherol could possibly alleviate allergic responses such asthma, whereas α-tocopherol has been found to be associated with better lung function (Cook-Mills, 2015). Mice studies have shown beneficial effects of α-tocopherol supplementation during pregnancy on offspring allergic disease outcome (Cook-Mills, 2015). Reduced maternal vitamin E and Zn intake during pregnancy has been associated with childhood allergic disease, for example eczema, asthma and wheeze development (Patelarou et al., 2011; West et al., 2012).

Vitamin E deﬁciency also contributes to the pathogenesis of allergic disease by reducing T-helper (Th)-cell secretion of interferon-gamma and/or increasing secretion of interleukin-4 or interleukin-5, downregulating interleukin-4 mRNA expression in human Th cells, increasing the production of prostaglandin E2, as well as inﬂuencing the development of regulatory T cells (Tr cells) (Patelarou et al., 2011).

In a cross-sectional study of 2633 United Kingdom adults, aged 18–70 years, with a mean vitamin E intake of 6.2 mg/day (SD 2.2), serum IgE and atopic sensitisation increased by approximately 5% per milligram decrease in vitamin E intake (Fogarty et al., 2000). In NHANES III, serum concentrations of α-carotene, β-cryptoxanthin and vitamin E in 5742 adults were beneficially associated with atopic sensitisation (OR 1 SD difference 95% CI); 0.95 (0.91–0.99), 0.89 (0.83–0.95) and 0.93 (0.87–0.99), respectively (McKeever et al., 2004).

A randomised control trial (RCT) conducted by Fairris et al. (1989) supplemented 40 adults with atopic dermatitis with 400 mg/day vitamin E or placebo for 12 weeksand found no association with any clinical improvement.Another RCT supplementing 112 people with allergic rhinitis with 800 mg/day vitamin E or placebo during the pollen season found vitamin E to be associated with modest improvements in patient reported nasal symptoms; no improvements in many other allergic rhinitis outcomes were found(Shahar

Fatty acid and micronutrient intake and status in association with allergy among pregnant urban women in South Africa