This review brings together human and animal studies and reviews that examine the possible role of maternal vitamin B12 (B12) on fetal growth and its programming for susceptibility to chronic disease. A selective literature review was undertaken to identify studies and reviews that investigate these issues, particularly in the context of a vegetarian diet that may be low in B12 and protein and high in carbohydrate. Evidence is accumulating that maternal B12 status influences fetal growth and development. Low maternal vitamin B12 status and protein intake are associated with increased risk of neural tube defect, low lean mass and excess adiposity, increased insulin resistance, impaired neurodevelopment and altered risk of cancer in the offspring. Vitamin B12 is a key nutrient associated with one carbon metabolic pathways related to substrate metabolism, synthesis and stability of nucleic acids and methylation of DNA which regulates gene expression. Understanding of factors regulating maternal–fetal one carbon metabolism and its role in fetal programming of non communicable diseases could help design effective interventions, starting with maternal nutrition before conception.
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Freinkel N . Banting Lecture 1980. Of pregnancy and progeny. Diabetes 1980; 29: 1023–1035.
Dominguez-Salas P, Cox SE, Prentice AM, Hennig BJ, Moore SE . Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 2012; 71: 154–165.
Fowden AL, Forhead AJ, Coan PM, Burton GJ . The placenta and intrauterine programming. J Neuroendocrinol 2008; 20: 439–450.
Gluckman PD, Hanson MA, Bateson P, Beedle AS, Law CM, Bhutta ZA et al. Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet 2009; 373: 1654–1657.
Barker DJ . Fetal origins of coronary heart disease. BMJ 1995; 311: 171–174.
Crider KS, Bailey LB, Berry RJ . Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 2011; 3: 370–384.
Koebnick C, Hoffmann I, Dagnelie PC, Heins UA, Wickramasinghe SN, Ratnayaka ID et al. Long-term ovo-lacto vegetarian diet impairs vitamin B-12 status in pregnant women. J Nutr 2004; 134: 3319–3326.
Ray JG, Wyatt PR, Thompson MD, Vermeulen MJ, Meier C, Wong PY et al. Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population. Epidemiology 2007; 18: 362–366.
Scott JM . Folate and vitamin B12. Proc Nutr Soc 1999; 58: 441–448.
Kalhan SC . Metabolism of methionine in vivo: impact of pregnancy, protein restriction, and fatty liver disease. Nestle Nutr Workshop Ser Pediatr Program 2009; 63: 121–131. discussion 131-123, 259-168.
Mato JM, Martinez-Chantar ML, Lu SC . Methionine metabolism and liver disease. Annu Rev Nutr 2008; 28: 273–293.
Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007; 104: 19351–19356.
Lillycrop KA . Effect of maternal diet on the epigenome: implications for human metabolic disease. Proc Nutr Soc 2011; 70: 64–72.
Jiménez-Chillarón JC, Díaz R, Martínez D, Pentinat T, Ramón-Krauel M, Ribó S et al. The role of nutrition on epigenetic modifications and their implications on health. Biochimie 2012; 94: 2242–2263.
Shane B . Folate and vitamin B12, metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms. Food Nutr Bull 2008; 29: S5–S16.
Brada N, Gordon MM, Wen J, Alpers DH . Transfer of cobalamin from intrinsic factor to transcobalamin II. J Nutr Biochem 2001; 12: 200–206.
World Health Organisation. Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food Nutr Bull 2008; 29: S238–S244.
Herrmann W, Obeid R, Schorr H, Geisel J . The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. Curr Drug Metab 2005; 6: 47–53.
Mason JB . Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr 2003; 133: 941S–947S.
Bhat DS, Thuse NV, Lubree HG, Joglekar CV, Naik SS, Ramdas LV et al. Increases in plasma holotranscobalamin can be used to assess vitamin B-12 absorption in individuals with low plasma vitamin B-12. J Nutr 2009; 139: 2119–2123.
Bor MV, Nexo E, Hvas AM . Holo-transcobalamin concentration and transcobalamin saturation reflect recent vitamin B12 absorption better than does serum vitamin B12. Clin Chem 2004; 50: 1043–1049.
Herrmann W, Schorr H, Obeid R, Geisel J . Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr 2003; 78: 131–136.
Fowden AL, Giussani DA, Forhead AJ . Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda) 2006; 21: 29–37.
Friso S, Choi SW . Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 2005; 6: 37–46.
Barbosa PR, Stabler SP, Machado ALK, Braga RC, Hirata RDC, Hirata MH et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr 2008; 62: 1010–1021.
Fowden AL, Giussani DA, Forhead AJ . Endocrine and metabolic programming during intrauterine development. Early Hum Dev 2005; 81: 723–734.
Harding JE, Johnston BM . Nutrition and fetal growth. Reprod Fertil Dev 1995; 7: 539–547.
Ciappio ED, Mason JB, Crott JW . Maternal one-carbon nutrient intake and cancer risk in offspring. Nutr Rev 2011; 69: 561–571.
Yajnik CS, Deshpande SS, Lubree HG, Naik SS, Bhat DS, Uradey BS et al. Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians. J Assoc Physicians India 2006; 54: 775–782.
Shetty PS . Nutrition transition in India. Public Health Nutr 2002; 5: 175–182.
Metayer S, Seiliez I, Collin A, Duchene S, Mercier Y, Geraert PA et al. Mechanisms through which sulfur amino acids control protein metabolism and oxidative status. J Nutr Biochem 2008; 19: 207–215.
Ingenbleek Y, McCully KS . Vegetarianism produces subclinical malnutrition, hyperhomocysteinemia and atherogenesis. Nutrition 2012; 28: 148–153.
Smith AD, Kim YI, Refsum H . Is folic acid good for everyone? Am J Clin Nutr 2008; 87: 517–533.
Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 2008; 51: 29–38.
Kelley DE, Goodpaster BH, Storlien L . Muscle triglyceride and insulin resistance. Annu Rev Nutr 2002; 22: 325–346.
Rush EC, Freitas I, Plank LD . Body size, body composition and fat distribution: comparative analysis of European, Maori, Pacific Island and Asian Indian adults. Br J Nutr 2009; 102: 632–641.
van Steijn L, Karamali NS, Kanhai HH, Ariens GA, Fall CH, Yajnik CS et al. Neonatal anthropometry: thin-fat phenotype in fourth to fifth generation South Asian neonates in Surinam. Int J Obes (Lond) 2009; 33: 1326–1329.
Yajnik CS, Fall CH, Coyaji KJ, Hirve SS, Rao S, Barker DJ et al. Neonatal anthropometry: the thin-fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord 2003; 27: 173–180.
Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L 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.
Rao S, Kanade AN, Yajnik CS, Fall CH . Seasonality in maternal intake and activity influence offspring's birth size among rural Indian mothers—Pune Maternal Nutrition Study. Int J Epidemiol 2009; 38: 1094–1103.
Dror DK, Allen LH . Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev 2008; 66: 250–255.
Chambers JC, Obeid OA, Refsum H, Ueland P, Hackett D, Hooper J et al. Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian Asian and European men. Lancet 2000; 355: 523–527.
Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU, Luthra K et al. Hyperhomocysteinemia, and low intakes of folic acid and vitamin B12 in urban North India. Eur J Nutr 2002; 41: 68–77.
Antony AC . Vegetarianism and vitamin B-12 (cobalamin) deficiency. Am J Clin Nutr 2003; 78: 3–6.
Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the USA 2008; 105: 17046–17049.
Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 2009; 4: e7845.
Waterland RA, Kellermayer R, Laritsky E, Rayco-Solon P, Harris RA, Travisano M et al. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genetics 2010; 6: e1001252.
Hoet JJ, Hanson MA . Intrauterine nutrition: its importance during critical periods for cardiovascular and endocrine development. J Physiol 1999; 514 (Pt 3), 617–627.
Frery N, Huel G, Leroy M, Moreau T, Savard R, Blot P et al. Vitamin B12 among parturients and their newborns and its relationship with birthweight. Eur J Obstet Gynecol Reprod Biol 1992; 45: 155–163.
Lindblad B, Zaman S, Malik A, Martin H, Ekstrom AM, Amu S et al. Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses. Acta Obstet Gynecol Scand 2005; 84: 1055–1061.
Muthayya S, Dwarkanath P, Mhaskar M, Mhaskar R, Thomas A, Duggan C et al. The relationship of neonatal serum vitamin B12 status with birth weight. Asia Pac J Clin Nutr 2006; 15: 538–543.
Muthayya S, Dwarkanath P, Thomas T, Vaz M, Mhaskar A, Mhaskar R et al. Anthropometry and body composition of south Indian babies at birth. Public Health Nutr 2006; 9: 896–903.
Muthayya S, Kurpad AV, Duggan CP, Bosch RJ, Dwarkanath P, Mhaskar A et al. Low maternal vitamin B12 status is associated with intrauterine growth retardation in urban South Indians. Eur J Clin Nutr 2006; 60: 791–801.
Obeid R, Herrmann W . Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects. Clin Chem Lab Med 2005; 43: 1052–1057.
Yajnik CS, Deshpande SS, Panchanadikar AV, Naik SS, Deshpande JA, Coyaji KJ et al. Maternal total homocysteine concentration and neonatal size in India. Asia Pac J Clin Nutr 2005; 14: 179–181.
Hogeveen M, Blom HJ, den Heijer M . Maternal homocysteine and small-for-gestational-age offspring: systematic review and meta-analysis. Am J Clin Nutr 2012; 95: 130–136.
Dasarathy J, Gruca LL, Bennett C, Parimi PS, Duenas C, Marczewski S et al. Methionine metabolism in human pregnancy. Am J Clin Nutr 2010; 91: 357–365.
Katre P, Bhat D, Lubree H, Otiv S, Joshi S, Joglekar C et al. Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12 and high folate status. Asia Pac J Clin Nutr 2010; 19: 335–343.
Lubree H, Katre P, Joshi S, Bhat D, Deshukh U, Memane N et al. Child’s homocysteine concentration at 2 years is influenced by pregnancy vitamin B12 and folate status. J Dev Orig Hlth Dis 2012; 3: 32–38.
Wang ZP, Shang XX, Zhao ZT . Low maternal vitamin B(12) is a risk factor for neural tube defects: a meta-analysis. J Matern Fetal Neonatal Med 2012; 25: 389–394.
Morris MS, Jacques PF, Rosenberg IH, Selhub J . Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007; 85: 193–200.
Molloy AM, Kirke PN, Brody LC, Scott JM, Mills JL . Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull 2008; 29: S101–S111. discussion S112-105.
Louwman MW, van Dusseldorp M, van de Vijver FJ, Thomas CM, Schneede J, Ueland PM et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr 2000; 72: 762–769.
Black MM . Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 2008; 29: S126–S131.
Bhate V, Deshpande S, Bhat DS, Joshi N, Ladkat R, Watve S et al. Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children. Food Nutr Bull 2008; 29: 249–254.
Godbole K, Deshmukh U, Yajnik C . Nutrigenetic determinants of neural tube defects in India. Indian Pediatr 2009; 46: 467–475.
Godbole K, Gayathri P, Ghule S, Sasirekha BV, Kanitkar-Damle A, Memane N et al. Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India. Birth Defects Res A Clin Mol Teratol 2011; 91: 848–856.
Bower C . Folate and fetal abnormalities: the prevention of neural tube defects. Proc Nutr Soc Australia 1992; 17: 198–202.
Modi N, Thomas EL, Uthaya SN, Umranikar S, Bell JD, Yajnik C . Whole body magnetic resonance imaging of healthy newborn infants demonstrates increased central adiposity in Asian Indians. Pediatr Res 2009; 65: 584–587.
Yajnik CS, Lubree HG, Rege SS, Naik SS, Deshpande JA, Deshpande SS et al. Adiposity and hyperinsulinemia in Indians are present at birth. J Clin Endocrinol Metab 2002; 87: 5575–5580.
Yajnik CS, Deshmukh US . Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord 2008; 9: 203–211.
Krishnaveni GV, Hill JC, Veena SR, Bhat DS, Wills AK, Karat CL et al. Low plasma vitamin B12 in pregnancy is associated with gestational 'diabesity' and later diabetes. Diabetologia 2009; 52: 2350–2358.
Krishnaveni GV, Hill JC, Leary SD, Veena SR, Saperia J, Saroja A et al. Anthropometry, glucose tolerance, and insulin concentrations in Indian children: relationships to maternal glucose and insulin concentrations during pregnancy. Diabetes Care 2005; 28: 2919–2925.
Weaver LT . Rapid growth in infancy: balancing the interests of the child. J Pediatr Gastroenterol Nutr 2006; 43: 428–432.
Lovblad K, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G . Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr Radiol 1997; 27: 155–158.
Guerra-Shinohara EM, Paiva AA, Rondo PH, Yamasaki K, Terzi CA, D'Almeida V . Relationship between total homocysteine and folate levels in pregnant women and their newborn babies according to maternal serum levels of vitamin B12. BJOG 2002; 109: 784–791.
Selhub J . Public health significance of elevated homocysteine. Food Nutr Bull 2008; 29: S116–S125.
Yajnik CS . Nutritional control of fetal growth. Nutr Rev 2006; 64: S50–S51. discussion S72-91.
The assistance of Joseph Ding with the biochemistry is appreciated. The authors received no support in the form of grants and/or equipment and drugs for writing this review.
The authors declare no conflict of interest.
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Rush, E., Katre, P. & Yajnik, C. Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease. Eur J Clin Nutr 68, 2–7 (2014). https://doi.org/10.1038/ejcn.2013.232
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