Topic of the Month

Nutritional programming

October 1, 2011

Embryonic and fetal development, as well as the early life of a newborn, are periods of physiological plasticity during which environmental influences may produce long-term effects. Both undernutrition and overnutrition during these periods have been shown to change disease risk in adulthood. These effects are influenced by the type, timing and duration of inappropriate nutrition.

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Adequate maternal nutrition, including micronutrient intake, is now widely recognized as being essential for optimal development in the womb. Considerable interest is being shown for examining the way in which nutrition during pregnancy and after birth may interact in determining fetal and postnatal health. An understanding of the interaction between nutrient imbalance and alteration of gene expression is likely to be the key to optimizing future health outcomes.

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In pregnancy

There is increasing evidence that fetal exposure to macro- and micronutrient undernutrition is linked to a higher metabolic and cardiovascular disease risk in adult life. This process has been termed “fetal programming”. Human data concerning the effects of at various stages of pregnancy have been gleaned from retrospective epidemiological studies. Adult offspring of survivors of the Dutch famine of 1945 had an increased risk of impaired glucose tolerance and developing type 2 diabetes if their exposure to poor nutrition in the womb was in late gestation and an increased risk of coronary heart disease and dyslipidaemia if the exposure was early in gestation (1, 2). A retrospective study from The Gambia has linked exposure of unborn life to the “hungry season” with a higher rate of death due to infectious causes in early adulthood. This would increase the possibility that maternal undernutrition during pregnancy affects their offspring’s immune functions (3). Other studies have failed to confirm these findings (4).

Folate

Substantial literature is available regarding the association between folate deficiency in pregnancy and increased risk of premature delivery, low birth weight and neural tube defects (5). In a subgroup of the population, this may be because of an interaction between low folate status and genetic traits, such as variations (polymorphisms) in the methylenetetrahydrofolate reductase gene, which result in increased blood homocysteine levels when folate intake is low (6). High homocysteine concentrations in pregnancy are associated with adverse pregnancy outcomes and hypertensive disorders that can affect fetal growth (7, 8).

Vitamin B6

Gene expression, impacting cell differentiation and the development of organs can be regulated by mechanisms other than changes in the underlying DNA sequence, namely by so called ’epigenetic’ changes, such as ‘DNA methylation’ or ‘histone deacetylation’. Among the environmental conditions influencing gene expression, nutrition is one of the most important epigenetic factors. DNA methylation, for example, seems to depend on the availability of vitamins B6 as well as vitamin B12 and folate (9).

Vitamin B12

Vitamin B12 deficiency is also associated with high homocysteine concentrations (10), suggesting that low vitamin B12 status in pregnancy may also be a risk factor for neural tube defects (11). Since high homocysteine concentrations are themselves associated with an increased risk of cardiovascular disease, the link between low birth weight and later cardiovascular disease at a population level may be at least in part mediated via genetic variations in folate and B12 metabolism.

Vitamin D

Acting through its specific receptor, vitamin D can produce various biological effects on human health via genomic, non-genomic or hormonal mechanisms. Vitamin D deficiency in pregnant women is potentially associated with increased risk of preeclampsiainsulin resistance and gestational diabetes mellitus. In addition, experimental data also anticipate that vitamin D sufficiency is critical for fetal development, particularly for the brain and immunological functions. Thus, vitamin D deficiency during pregnancy may not only interfere with maternal skeletal preservation and fetal skeletal formation, but may also have an impact on fetal ‘imprinting’ that could affect chronic disease susceptibility soon after birth and later in life (12).

Other data have shown that maternal Vitamin D supplementation during pregnancy was associated with an increase in the gene expression, raising the levels of so-called ‘immunoglobuline-like transcipts’ in cord blood. This finding may point towards an early induction of immunological tolerance in the fetus by maternal vitamin D intake (13). The vitamin D receptor (VDR) seems to play an important role in several immune functions, e.g. by modulating T cell differentiation (14). Genetic variations of VDR are associated with immune-related diseases such as asthma.

Antioxidants

In epidemiologic studies of children and adults, several groups have reported associations between asthma and reduced intake and blood levels of dietary nutrients such as antioxidant vitamins C and E, as well as beta-carotene, selenium and zinc (15). However, supplementation with those antioxidants has not been consistently associated with improved asthma outcomes (16, 17). One possible explanation for the inconsistencies between epidemiologic and intervention studies is that dietary antioxidants primarily influence the development of asthma during a critical time period early in life. Studies have shown that low maternal vitamin E intake during pregnancy is associated with increased likelihood of wheezing and asthma in 5-year-old children (18). More recent findings support the concept of early fetal programming of respiratory disease. According to those, maternal vitamin E status may be one determinant for growth of the fetus and fetal lungs during early pregnancy (19).

Essential fatty acids

Research is investigating the complex roles of dietary fatty acids in regulating gene expression and intracellular communication. Accumulating evidence supports the hypothesis that maternal intakes of the omega-3 fatty acids docosanexaenic acid (DHA) and eicosapentaenic acid (EPA), as well as omega-6 fatty acids in gestation and lactation (maybe involving excess Omega-6 and inadequate Omega-3 fatty acids), can have an impact on the developing infant tissue lipids and metabolic pathways of cells that receive neuronal input. Further research in the field of metabolic programming is required to understand the need for different omega-3 and omega-6 fatty acids during fetal and infant life, as well as their roles with respect to development of energy balance and neurometabolism (20). One initial study indicates beneficial long-term neurophysiologic and neurobehavioral effects of adequate omega-3 fatty acid intakes during pregnancy on memory function in school-age children (21).

Calcium

A trial of maternal calcium supplementation has shown that blood pressure is lower in the 7-year-old offspring of calcium-supplemented mothers (22). A prospective cohort study has also found a strong association between low infant blood pressure at 6 months and the calcium intake that their mothers received via supplements (23).

Iron

Low iron status in pregnant women was found to be related to increased placental size (24). The significance of this upon the offspring’s later health is unknown, but an association between increased placental size and increased blood pressure in the offspring has been noted in epidemiological studies (25). A randomized double-blind clinical trial measuring iron levels with or without multi-micronutrient supplementation in pregnant women has shown no additional effect on birth weight from micronutrients over iron supplements alone (26).

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In infants

Although inappropriate nutrition in the womb can clearly affect the fetus in ways that impact later health, the extent to which these effects can be modified by the environment after birth (postnatal) is also of prime public health importance in order to minimize adverse health outcomes. The early postnatal period is also a period of physiological plasticity, although the timing of this “window of opportunity” may differ depending on the outcome of interest and may even be gender-specific. Very few human trials investigating the programming potential of micronutrients in infants’ diets are available to date. Such investigations require prolonged follow-ups, may be ethically difficult and are not always informed by accurate data regarding maternal nutrition during pregnancy (27).

Essential fatty acids

Recent findings indicate that variations of genes related to polyunsaturated fatty acid metabolism may be of relevance for human development and health. Common polymorphisms in the fatty acid desaturase (FADS) genes have been shown to significantly decrease omega-3 fatty acid concentrations in blood, breast milk and tissues during pregnancy and in children (28). In addition, polymorphisms in FADS seem to negatively influence the risk for developing allergic disorders and eczema, while diminishing the positive effect of breastfeeding on later cognitive development. Moreover, research suggests that omega-3 fatty acid supplementation in infants may decrease the risk of developing some manifestations of allergic disease later in life (29). However, further investigations would be necessary to confirm these potential early programming effects on the immune system.

References

  1. Ravelli A. C. et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet. 1998; 351:173–177.
  2. Roseboom T. J. et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart. 2000; 84:595–598.
  3. Moore S. E. et al. Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa. Int J Epidemiol. 1999; 28:1088–1095.
  4. Simondon K. B. et al. Season of birth is not associated with risk of early adult death in rural Senegal. Int J. Epidemiol. 2004; 33:130–136.
  5. Scholl T. O. and Johnson W. G. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000; 71(5):1295–1303.
  6. Kim K. N. et al. Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women. Eur J Clin Nutr. 2004 ; 58 :10–16.
  7. Calle M. de la et al. Homocysteine, folic acid and B-group vitamins in obstetrics and gynaecology. Eur J Obstet Gynecol Reprod Biol. 2003 ; 107:125–134.
  8. Steegers-Theunissen R. P. et al. Hyperhomocysteinemia, pregnancy complications, and the timing of investigation. Obstet Gynecol. 2004; 104:336–343.
  9. Chmurzynska A. Fetal Programming: link between early nutrition, DNA methylation, and complex diseases. Nutr Rev. 2010; 68(2)87–98.
  10. Refsum H. et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001; 74:233–241.
  11. Felix T. M. et al. Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil. Birth Defects Res. 2004; 70:459–463.
  12. Lapilonne A. Vitamin D deficiancy during pregnancy may impair maternal and fetal outcomes. Med Hypotheses. 2010; 74(1):71–75.
  13. Rochat M.K. et al. Maternal vitamin D intake during pregnancy increases gene expression of ILT3 and ILT4 in cord blood. Clin Exp Allergy. 2010; 40(5):786–794.
  14. Raby B.A. et al. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004; 170(10):1057–1065.
  15. Rubin R. N. Et al. Relationship of serum antioxidants to asthma prevalence in youth. Am J Respir Crit Care Med. 2004; 169:393–398.
  16. Ram F. S. et al. Vitamin C supplementation for asthma. Cochrane Database Syst Rev. 2004; 1.
  17. Allam M. F. and Lucane R. A. Selenium supplementation for asthma. Cochrane Database Syst Rev. 2004; 1.
  18. Devereux G. et al. Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. American Journal of Respiratory and Critical Care Medicine. 2006; 174:499–507.
  19. Turner S.W. et al. Associations between fetal size, maternal {alpha}-tocopherol and childhood asthma. Thorax. 2010; 65(5):391–397.
  20. Innis S.M. Metabolic programming of long-term outcomes due to fatty acid nutrition in early life.  Matern Child Nutr. 2011; 7 (2):112–123.
  21. Boucher O. et al. Neurophysiologic and neurobehavioral evidence of beneficial effects of prenatal omega-3 fatty acid intake on memory function at school age. Am J Clin Nutr. 2011; 93(5):1025–1037.
  22. Belizan J. M. et al. Long-term effect of calcium supplementation during pregnancy on the blood pressure of offspring: follow up of a randomised controlled trial. BMJ. 1997; 315:281–285.
  23. Gillman M. W. et al. Maternal calcium intake and offspring blood pressure. Circulation. 2004; 110:1990–1995.
  24. Hindmarsh P. C. et al. Effect of early maternal iron stores on placental weight and structure. Lancet. 2000; 356:719–723.
  25. Barker D. J. et al. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990; 301:259–262.
  26. Ramakrishnan U. et al. Multiple micronutrient supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation: a randomized controlled trial in a semirural community in Mexico. Am J Clin Nutr. 2003; 77:720–725.
  27. Buckley A. J. et al. Nutritional programming of adult disease. Cell Tissue Res. 2005; 322: 73–79.
  28. Glaser C. et al. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern Child Nutr. 2011; 7 (2):27–40.
  29. Calder P.C. et al. Is there a role for fatty acids in early life programming of the immune system?  Proc Nutr Soc. 2010; 69(3):373–380.