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For the scientific community

Introduction

Childhood asthma became a very common condition in the UK during the 1980 and 1990s and a number of hypotheses were put forward to explain the “asthma epidemic”.

In 1994, Anthony Seaton and colleagues suggested that changes in the nation's diet might explain the rise in childhood asthma1.

Earlier epidemiology studies demonstrated nutritional deficiencies in people with asthma compared to controls but intervention studies in people with established asthma consistently failed to demonstrate any clinical benefit.

One explanation for this apparent inconsistency between epidemiology and intervention studies might be that dietary deficiencies may be relevant to asthma causation de novo and if this was true, then interventions in established asthma were too late. What was required was evidence that dietary exposures before the onset of symptoms were related to later asthma.

In 1997 we established the SEATON (Study of Eczema and Asthma To Observe the effects of Nutrition) cohort of children, to investigate whether maternal antioxidant intake during pregnancy modifies susceptibility to childhood asthma and atopic disease2.

Although originally focused on antioxidants, the scope of the study has widened to include other nutrients with the potential to influence immunological and lung development, and childhood diet.  Also, to make best use of the data collected, we are using the SEATON cohort to study links between early life exposures and common non-communicable conditions such as obesity, hypertension and anxiety and depression.

Study Overview

The SEATON cohort comprises 1924 singleton children born to 2000 pregnant women representative of the local obstetric population, recruited at 12 weeks gestation between 1997 and 1999.

At enrolment, the women were characterised by a questionnaire and skin prick testing. Maternal diet during pregnancy was quantified by blood nutrient levels (determined at 12 weeks gestation) and a food frequency questionnaire (FFQ) administered at 32 weeks gestation.

At birth, cord blood mononuclear cell (CBMC) responses were quantified3-5 and we reported that low maternal vitamin E intake during pregnancy was associated with increased CBMC proliferative responses to allergenic stimuli5.This finding has since been replicated6.

The cohort children were followed up at 6, 12 and 24 months by postal questionnaire. From this phase of the study we reported that low maternal vitamin E intake during pregnancy was associated with increased wheeze and eczema outcomes in children at the age of 2 years2.

We also reported that low maternal plasma selenium concentration during pregnancy and cord blood plasma selenium at birth was associated with an increased likelihood of wheeze and persistent wheeze in 2-year-old children7 supporting the association reported by the ALSPAC study8.

The scope of the 5-year SEATON follow up was increased to include childhood diet and objective measures of ventilatory function, exhaled nitric oxide and atopic skin prick tests. We demonstrated that maternal vitamin E intake and/or plasma a-tocopherolconcentration during pregnancy is beneficially associated with the 5-year outcomes of: wheeze, asthma, FEV1,exhaled nitric oxide and atopic sensitisation9. Although maternal vitamin E intake during pregnancy and childhood vitamin E intake at 5-years were weakly positively correlated, childhood intake was not associated with any 5-year outcomes.

Extrapolation of the SEATON study to data from the General Household10 and the National Diet and Nutrition Surveys11 suggest that declining UK vitamin E intake could have been responsible for a doubling of childhood asthma prevalence between 1950 and 2000.

The 5-year follow up of the SEATON cohort also demonstrated that low maternal zinc intake during pregnancy was associated with increased likelihood of asthma and eczema9. Zinc is not an antioxidant, however like vitamin E, zinc influences fetal lung growth and Th-cell differentiation in animal models12,13. The findings with zinc led us to investigate vitamin D because of its potential to influence fetal lung growth and regulatory T-cell activity14,15, and we recently reported that low maternal vitamin D intake during pregnancy is associated with increased wheezing outcomes in 5-year-old children16.

Confidence in our findings has been reinforced by reports of associations between vitamin E, vitamin D, zinc and respiratory outcomes by Project Viva in the United States that established a birth cohort in a population with markedly different socio-economic, smoking, ethnic and dietary profiles to the SEATON study17.

Although the SEATON cohort was established to investigate maternal antioxidant intake during pregnancy, the results to date support the notion that non-antioxidant properties of nutrients on airway development and Th-cell differentiation are likely to be important in the development of asthma in 5-year-old children18. Moreover the associations between maternal vitamin E, vitamin D and zinc intakes appear to be independent of childhood intake of these nutrients at the age of 5-years9,14.

We obtained the routinely acquired fetal ultrasound measurements for the SEATON cohort in order to determine whether maternal nutrient intake during pregnancy may be influencing the risk for childhood asthma via an effect on antenatal lung development. We were the first group to demonstrate associations between maternal plasma vitamin E concentrations and first trimester fetal size19.

We also described associations between small antenatal fetal size and increased risk for asthma and obstructed lung function at five19 and ten years of age20. A second cohort has subsequently also found associations between antenatal growth and respiratory outcomes at four years of age21. In addition to confirming the associations between fetal size and respiratory outcomes seen at five years when the cohort was reassessed at ten years of age, we have also seen how maternal vitamin D and E intakes are related to wheeze to ten years of age22.  At fifteen years of age we observed that increased maternal  dietary vitamins D and E were associated with reduced early onset wheeze, but not later onset wheeze23.  Also the association between reduced first trimester size and increase risk for asthma but not eczema persisted24. 

The SEATON cohort is one of very few cohorts around the world which has captured maternal dietary exposures and also one of a small number which has antenatal fetal measurements. This is the only study with both detailed maternal dietary intake and fetal measurements and as such is a particularly valuable resource to study early origins of asthma, and also potentially other common chronic non communicable conditions such as hypertension, obesity, anxiety and depression.

The cohort members are now approaching 25 years of age and we know that this is a very relevant time to invite these young people to take part in dietary and respiratory assessments. The relevance is in part due to the fact that out lungs reach a peak in performance around the age of 25.  Additionally  life style factors which may alter respiratory outcomes, e.g. smoking, may have changed since we last met the cohohrt members when they were 15 years old..

References

  1. Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49:11. 
  2. Martindale S, McNeill G, Devereux G, Campbell D, Russell G, Seaton A. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 2005; 171:121-8.
  3. Devereux G, Hall AM, Barker RN. Measurement of T-helper cytokines secreted by cord blood mononuclear cells in response to allergens. J Immunological Methods 2000; 234:13-22.
  4. Devereux G, Seaton A, Barker RN. In Utero sensitisation of allergen specific T-helper cells. Clin Exp Allergy 2001;31:1686-1695.
  5. Devereux G, Barker RN, Seaton A. Ante-natal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002;32:43-50.
  6. Litonjua AA, Tantisira KG, Finn PW, et al. Maternal antioxidant intake during pregnancy and cord blood lymphoproliferative responses. Am J Resp Crit Care Med 2004; 169:A501.
  7. Devereux G, McNeill G, Newman G, Seaton A. Maternal selenium status during pregnancy and respiratory symptoms in the first two years of life. Clin Exp Allergy 2007; 37:1000-8.
  8. Shaheen, SO, Newson, RB, Henderson, AJ, Emmett, PM, Sherriff A, Cooke M. Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema. Eur Respir J 2004; 24: 292-7.
  9. Devereux G, Turner SW, Craig LCA, McNeill G, Martindale S, Harbour PJ, Helms PJ, Seaton A. Reduced maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Respir Crit Care Med 2006; 174: 499-507.
  10. National Food Survey. Household consumption of selected foods from 1942 onwards. http://statistics.defra.gov.uk/esg/publications/nfs/datasets/allfood.xls.
  11. Henderson L, Irving K, Gregory J, Bates CJ, Prentice A, Perks J et al. The National Diet and Nutrition Survey: adults aged 19 to 64 years. HMSO. 2003; http://www.food.gov.uk/multimedia/pdfs/ndnsv3.pdf.
  12. Vojnik C, Hurley LS. Abnormal prenatal lung development resulting from maternal zinc deficiency in rats. J Nutrition 1977; 107: 862-72.
  13. Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infectious Diseases 2000; 182 suppl 1: S62-8.
  14. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005;128:3792-8.
  15. Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006;116:146-55.
  16. Devereux G, Litonjua AA, Turner SW, Craig LCA, McNeill G, Martindale S, et al. Maternal vitamin D intake during pregnancy and early childhood wheeze. Am J Clin Nutrition; 2007:85:853-9
  17. Litonjua AA, Rifas-Shiman S, Ly NP, Tantisira KG, Rich-Edwards JW, Weiss ST et al. Maternal antioxidant intake in pregnancy and wheezing illnesses at 2 years of age. Am J Clin Nutrition 2006; 84:903-11.
  18. Devereux G. The increase in the prevalence of asthma and allergy: food for thought. Nature Reviews Immunology, 2006; 6:869-74.
  19. Turner SW, Campbell D, Smith N, Craig LC, McNeill G, Forbes SH, Harbour PJ, Seaton A, Helms PJ, Devereux GS. Associations between fetal size, maternal alpha-tocopherol and childhood asthma. Thorax 2010;55:555–561.
  20. Turner S, Prabhu N, Danielian P, et al. First and Second Trimester Fetal Size and Asthma Outcomes at Age Ten Years. Am J Respir Crit Care Med 2011;184:407-413
  21. Pike KC, Crozier SR, Lucas JS, et al. Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years. Thorax 2010; 65:1099-1106
  22. Allan KM, Prabhu N, Craig LCA, et al. Maternal intakes of vitamin D and E during pregnancy are associated with asthma in children. Eur Resp J. 2015;45:1027–1036.
  23. Turner S, Fielding S, Devereux G. First trimester fetal size and prescribed asthma medication at 15 years of age. Eur Resp J. 2018;51:1701509
  24. Devereux G, Craig L, Seaton A, Turner S. Maternal vitamin D and E intakes in pregnancy and asthma to age 15 years: A cohort study. Pediatr Pulmonol. 2019;54:11–19