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Review Article

Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I – Folate, Vitamin B12, Vitamin B6

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Pages 1323-1343 | Received 23 Dec 2009, Accepted 30 Dec 2009, Published online: 07 Apr 2010

References

  • Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90–96.
  • Henshaw S. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30:24–29, 46.
  • Bailey LB. Folic acid. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2007. p. 387. (Fig. 1).
  • Hsieh CL. Dependence of transcriptional repression on CpG methylation density. Mol Cell Biol 1994;14:5487–5494.
  • Razin A. CpG methylation, chromatin structure and gene silencing – a three-way connection. EMBO J 1998;17:4905–4908.
  • Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247–257.
  • Bailey LB. Folic acid. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2007. p. 393. (Fig. 2).
  • McNulty H, Pentieva K. Folate bioavailability. In: Bailey LB, editor. Folate in health and disease. 2nd ed. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 25–47.
  • Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 2005;82:442–450.
  • Sauberlich HE, Kretsch MJ, Skala JH, Johnson HL, Taylor PC. Folate requirement and metabolism in nonpregnant women. Am J Clin Nutr 1987;46:1016–1028.
  • Institute of Medicine and Committee (IOM). Dietary reference intake: folate, other B vitamins and choline. Washington, DC: National Academy Press; 1998.
  • Stabler SP. Clinical folate deficiency. In: Bailey LB, editor. Folate in health and disease, 2nd ed. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 409–428.
  • Ek J. Plasma and red cell folate values in newborn infants and their mothers in relation to gestational age. J Pediatr 1980;97:288–292.
  • Chanarin I. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. The megaloblastic anaemias. London: Blackwell; 1969. pp. 786–829.
  • Bruinse HW, van der Berg H, Haspels AA. Maternal serum folacin levels during and after normal pregnancy. Eur J Obstet Gynecol Reprod Biol 1985;20:153–158.
  • Qvist I, Abdulla M, Jagerstad M, Svensson S. Iron, zinc and folate status during pregnancy and two months after delivery. Acta Obstet Gynecol Scand 1986;65:15–22.
  • Tamura T, Picciano MF. Folate and human reproduction. Am J Clin Nutr 2006;83:993–1016.
  • Takimoto H, Mito N, Umegaki K, Ishiwaki A, Kusama K, Abe S, Yamawaki M, Fukuoka H, Ohta C, Yoshiike N. Relationship between dietary folate intakes, maternal plasma total homocysteine and B-vitamins during pregnancy and fetal growth in Japan. Eur J Nutr 2007;46:300–306.
  • Wallace JM, Bonham MP, Strain JJ, Duffy EM, Robson PJ, Ward M, McNulty H, Davidson PW, Myers GJ, Shamlaye CF, et al Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study. Am J Clin Nutr 2008;87:391–397.
  • Bailey LB. New standard for dietary folate intake in pregnant women. Am J Clin Nutr 2000;71 (5 Suppl):1304S–1307S.
  • Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med 1999;341:1509–1519.
  • Centers for Disease Control and Prevention. Spina bifida and anencephaly before and after folic acid mandate: United States, 1995–1996 and 1999–2000. MMWR Morb Mortal Wkly Rep May 7; 2004/53:362–365.
  • Global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge: Harvard School of Health; 1996.
  • Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong L-YC. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. J Am Med Assoc 2001;285:2981–2986.
  • Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, Hong S, Wang T, Li Z. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol 2006;76:237–240.
  • Prevention of Neural Tube Defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131–137.
  • Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–1835.
  • Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recommendation Report. September 11, 1992/41(RR-14);001.
  • US Preventive Services Task Force. Folic acid for the prevention of neural tube defects: US preventive services task force recommendation statement. Ann Intern Med 2009;150:626–631.
  • Australian National Health and Medical Research Council, New Zealand Ministry of Health. Nutrient reference values for Australia and New Zealand including recommended dietary intakes. Canberra (Australia): National Health and Medical Research Council; 2006.
  • Food Safety Authority of Ireland RDA Working Group. Recommended dietary allowances for Ireland. Dublin (Ireland): Food Safety Authority of Ireland; 1999.
  • Health Council of the Netherlands. Towards an optimal use of folic acid. The Hague (The Netherlands): Health Council of the Netherlands. 2008. Publication No. 2008/02E.
  • German Nutrition Society, Austrian Nutrition Society, Swiss Society for Nutrition Research, Swiss Nutrition Association. Reference values for nutrient intake. 1st English Ed. Frankfort/Main:Umschau Braus GmbH: German Nutrition Society; 2002.
  • Scientific Advisory Committee on Nutrition 2006. Folate and Disease Prevention. Norwich, UK: The Stationery Office; 2006.
  • Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. J Am Med Assoc 1988;260:3141–3145.
  • Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. J Am Med Assoc 1989;262:2847–2852.
  • Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. J Am Med Assoc 1993;269:1257–1261.
  • Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995;6:219–226.
  • Khoury MJ, Shaw GM, Moore CA, Lammer EJ, Mulinare J. Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? Data from two population-based case–control studies. Am J Med Genet 1996;61:30–36.
  • Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, et al Prevention of neural-tube defects with folic acid in China. China–US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999;341:1485–1490.
  • Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, Read AP, Fielding DW. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;315:339–340.
  • Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects. Arch Dis Child 1976;51:944–950.
  • Mills JL, Rhoads GG, Simpson JL, Cunningham GC, Conley MR, Lassman MR, Walden ME, Depp OR, Hoffman HJ. The absence of a relation between the periconceptional use of vitamins and neural-tube defects. National Institute of Child Health and Human Developmental and Neural Tube Defects Study Group. N Engl J Med 1989;321:430–435.
  • Centers for Disease Control and Prevention. Effectiveness in disease and injury prevention use of folic acid for prevention of spina bifida and other neural tube defects – 1983–1991. MMWR Morb Mortal Wkly Rep August 02; 1991/41. pp. 513–516.
  • Centers for Disease Control and Prevention. Use of supplements containing folic acid among women of childbearing age-United States, 2007. MMWR Morb Mortal Wkly Rep Jan. 11,2008/57. pp. 5–8.
  • Centers for Disease Control and Prevention. Trends in wheat flour fortification with folic acid and iron-worldwide, 2004 and 2007. MMWR Morb Mortal Wkly Rep January 11,2008/57. pp. 8–10.
  • Berry RJ, Bailey, LB, Mulinare, Bower C, Dary O; Folic Acid Working Group. Fortification of flour with folic acid. Food and Nutrition Board. Washington, DC; 2010.
  • Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid, Final Rule. 21 CFR Parts 136, 137, and 139. Federal Register. 1996 March 5, 1996 64. pp. 8781–8797.
  • Yang Q-H, Carter HK, Mulinare J, Berry RJ, Friedman JM, Erickson JD. Race–ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001–2002. Am J Clin Nutr 2007;85:1409–1416.
  • Kauwell GPA, Diaz ML, Yang Q, Bailey. Folate: recommended intakes, consumption, and status. In: Bailey LB, editor. Folate in health and disease. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 467–490.
  • Pfeiffer CM, Johnson CL, Jain RB, Yetley EA, Picciano MF, Rader JI, Fisher KD, Mulinare J, Osterloh J. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004. Am J Clin Nutr 2007;86:718–727.
  • Williams LJ, Rasmussen SA, Flores A, Kirby RS, Edmonds LD. Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995–2002. Pediatrics 2005;116:580–586.
  • Centers for Disease Control and Prevention. Trends in folic acid supplement intake among women of reproductive age – California, 2002–2006. MMWR Morb Mortal Wkly Rep October 26, 2007/56. 1106–1109.
  • Berry RJ, Mulinare J, Hamner HC. Folic acid fortification: neural tube defect risk reduction global perspective. In: Bailey LB, editor. Folate in health and disease. 2nd ed. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 179–204.
  • Office of Disease Prevention and Health Promotion. US Department of Health and Human Services. Healthy People 2010; Available from: http://www.healthypeople.gov/.
  • Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. J A Med Assoc 1995;274:1698–1702.
  • Cuskelly GJ, McNulty H, Scott JM. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. Lancet 1996;347:657–659.
  • Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 2005;81:1213S–1217S.
  • Botto LD, Mulinare J, Erickson JD. Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps. Am J Med Genet 2003;121A:95–101.
  • Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996;62:179–183.
  • Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191:790–794.
  • Shaw GM, O'Malley CD, Wasserman CR, Tolarova HM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995;59:536–545.
  • Botto LD, Khoury MJ, Mulinare J, Erickson JD. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 1996;98:911–917.
  • Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal multivitamin use. Am J Epidemiol 2000;151:878–884.
  • Scanlon KS, Ferencz C, Loffredo CA, Wilson PD, Correa-Villasenor A, Khoury MJ, Willett WC. Preconceptional folate intake and malformations of the cardiac outflow tract. Baltimore–Washington Infant Study Group. Epidemiology 1998;9:95–98.
  • Werler MM, Hayes C, Louik C, Shapiro S, Mitchell AA. Multivitamin supplementation and risk of birth defects. Am J Epidemiol 1999;150:675–682.
  • Ionescu-Ittu R, Marelli AJ, Mackie AS, Pilote L. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ 2009;338:b1673.
  • Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Åbyholm F, Vindenes H, Vollset SE, Drevon CA. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 2007;334:464.
  • Hayes C, Werter MM, Willett WC, Mitchell AA. Case–control study of periconceptional folic acid supplementation and oral clefts. Am J Epidemiol 1996;143:1229–1234.
  • Whiteside MG, Ungar B, Path MC, Cowling DC, Path FC. Iron, folic acid and vitamin B12 levels in normal pregnancy, and their influence on birth-weight and the duration of pregnancy. Med J Aust 1968;1:338–342.
  • Martin JD, Davis RE, Stenhouse N. Serum folate and vitamin B12 levels in pregnancy with particular reference to uterine bleeding and bacteriuria. J Obstet Gynaecol Br Commonw 1967;74:697–701.
  • Tchernia G, Blot I, Rey A, Kaltwasser JP, Zittoun J, Papiernik E. Maternal folate status, birthweight and gestational age. Dev Pharmacol Ther 1982;4 Suppl:58–65.
  • Malinow MR, Rajkovic A, Duell PB, Hess DL, Upson B. The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism. Am J Obstet Gynecol 1998:178:228–233.
  • Baumslag N, Edelstein T, Metz J. Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy. Br Med J 1970;1:16–17.
  • Blot I, Papiernik E, Kaltwasser JP, Werner E, Tchernia G. Influence of routine administration of folic acid during pregnancy. Gynecol Obstet Invest 1981;12:294–304.
  • Fleming AF, Martin JD, Hahnel R, Westlake AJ. Effects of iron and folic acid antenatal supplements on maternal haematology and fetal wellbeing. Med J Aust 1974;2:429–436.
  • Fletcher J, Gurr A, Fellingham FR, Prankerd TAJ, Brant HA, Menzies DN. The value of folic acid supplements in pregnancy. J Obstet Gynaecol Br Commonw 1971;78:781–785.
  • Giles PF, Harcourt AG, Whiteside MG. The effect of prescribing folic acid during pregnancy on birth-weight and duration of pregnancy. A double blind trial. Med J Aust 1971;2:17–21.
  • Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GDV, Eddleman K, Gross S, Dugoff L, Craigo SD, et al Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Med 2009;6:e1000061.
  • Giovannucci E. Epidemiologic Studies of folate and colorectal neoplasia: a review. J Nutr 2002;132:2350S–2355S.
  • Giovannucci E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 2004;134:2475S–2481S.
  • Mason JB, Choi SW. Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol 2005;35:235–241.
  • Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325–1329.
  • Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, et al Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. For the Polyp Prevention Study Group. J Am Med Assoc 2007;297:2351–2359.
  • Mason JB. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev 2009;67:206–212.
  • Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR; ukCAP Trial Group. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008;134:29–38.
  • Jaszewski R, Misra S, Tobi M, Ullah N, Naumoff JA, Kucuk O, Levi E, Axelrod BN, Patel BB, Majumdar APN. Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World J Gastroenterol 2008;14:4492–4498.
  • Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer FE, Willett WC. A prospective study of folate intake and the risk of breast cancer. J Am Med Assoc 1999;281:1632–1637.
  • Sellers TA, Kushi LH, Cerhan JR, Vierkant RA, Gapstur SM, Vachon CM, Olson JE, Therneau TM, Folsom AR. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12:420–428.
  • Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:266–269.
  • Cho E, Holmes M, Hankinson SE, Willett WC. Nutrients involved in one-carbon metabolism and risk of breast cancer among premenopausal women. Cancer Epidemiol Biomarkers Prev 2007;16:2787–2790.
  • Stolzenberg-Solomon RZ, Chang S-C, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG. Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr 2006;83:895–904.
  • Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort. Am J Clin Nutr 2007;86:434–443.
  • Hannibal L, Glushchenko AV, Jacobsen DW. Folate and vascular disease: basic mechanisms. In: Bailey LB, editor. Folate in health and disease. 2nd ed. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 291–323.
  • B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 2006;151:282–287.
  • Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 2006;113:1335–1343.
  • Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. The Lancet 2007;369:1876–1882.
  • Chen J, Xu X, Liu A, Ulrich C. Folate and cancer: epidemiological perspective. In: Bailey LB, editor. Folate in health and disease. 2nd ed. Boca Raton, FL: CRC Press, Taylor and Francis Group; 2009. pp. 205–233.
  • Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V, Factor-Litvak P, Levy D, Alam S, Islam M, Parvez F, et al Folic acid supplementation lowers blood arsenic. Am J Clin Nutr 2007;86:1202–1209.
  • Czeizel AE, Metneki J, Istvan D. Higher rate of multiple births after periconceptional vitamin supplementation (correspondence). N Eng J Med 1994;330:1687–1688.
  • Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4:63–66.
  • Li Z, Gindler J, Wang H, Berry R, Li S, Correa A, Zheng J, Erickson J, Wang Y. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003;361:380–384.
  • Kucik J, Correa A. Trends in twinning rates in metropolitan Atlanta before and after folic acid fortification. J Reprod Med 2004;49:707–712.
  • Lawrence JM, Watkins ML, Chiu V, Erickson JD, Petitti DB. Food fortification with folic acid and rate of multiple births, 1994–2000. Birth Defects Res A Clin Mol Teratol 2004;70:948–952.
  • Signore C, Mills JL, Cox C, Trumble AC. Effects of folic acid fortification on twin gestation rates. Obstet Gynecol 2005;105:757–762.
  • Waller DK, Tita ATN, Annegers JF. Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998. Paediatr Perinat Epidemiol 2003;17:378–383.
  • Haggarty P, McCallum H, McBain H, Andrews K, Duthie S, McNeill G, Templeton A, Haites N, Campbell D, Bhattacharya S. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 2006;367:1513–1519.
  • Wolff T, Witkop CT, Miller T, Syed SB. Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the US preventive services task force. Ann Intern Med 2009;150:632–639.
  • Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, et al Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189–194.
  • Green RM, Miller JW. Vitamin B12. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2007. p. 416. (Fig. 3).
  • Green R, Miller JW. Vitamin B12. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. Boca Raton, FL, CRC Press, Taylor & Francis Group; 2007. pp. 413–457.
  • Green R, Miller J. Vitamin B12. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2007. p. 422. (Figure 4).
  • Clarke R, Sherliker P, Hin H, Nexo E, Hvas AM, Schneede J, Birks J, Ueland PM, Emmens K, Scott JM, et al Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin Chem 2007;53:963–970.
  • Hvas AM, Nexo E. Holotranscobalamin – a first choice assay for diagnosing early vitamin B deficiency? J Intern Med 2005;257:289–298.
  • Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev 2008;66:250–255.
  • Brown AL, von Castel-Roberts K, Maneval DR, Shelnutt KP, Portier KM, Siega-Riz A-M, Kauwell GPA, Bailey LB. Dietary vitamin B12 intake and status of young adults consuming vegetarian or beef-containing diets. FASEB J 2006;20: A620–a.
  • Millet P, Guilland JC, Fuchs F, Klepping J. Nutrient intake and vitamin status of healthy French vegetarians and nonvegetarians. Am J Clin Nutr 1989;50:718–727.
  • 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.
  • Helman AD, Darnton-Hill I. Vitamin and iron status in new vegetarians. Am J Clin Nutr 1987;45:785–789.
  • Koebnick C, Hoffmann I, Dagnelie PC, Heins UA, Wickramasinghe SN, Ratnayaka ID, Gruendel S, Lindemans J, Leitzmann C. Long-term ovo-lacto vegetarian diet impairs Vitamin B-12 status in pregnant women. J Nutr 2004;134:3319–3326.
  • Krajcovicová-Kudlácková M, Blazícek P, Kopcová J, Béderová A, Babinská K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab 2000;44:135–138.
  • Allen LH. Folate and vitamin B12 status in the Americas. Nutr Rev 2004;62(6 Pt 2):S29–33; discussion S34.
  • Allen LH. Multiple micronutrients in pregnancy and lactation: an overview. Am J Clin Nutr 2005;81:1206S–1212S.
  • Glew RH, McCarthy DM, Vanderjagt DJ. Vitamin B12 deficiency: is it underestimated in pregnant women? Acta Obstet Gynecol Scand 2006;85:241–242.
  • Koc A, Kocyigit A, Soran M, Demir N, Sevinc E, Erel O, Mil Z. High frequency of maternal vitamin B12 deficiency as an important cause of infantile vitamin B12 deficiency in Sanliurfa province of Turkey. Eur J Nutr 2006;45:291–297.
  • Milman N, Byg KE, Bergholt T, Eriksen L, Hvas AM. Cobalamin status during normal pregnancy and postpartum: a longitudinal study comprising 406 Danish women. Eur J Haematol 2006;76:521–525.
  • Ray JG, Goodman J, O'Mahoney PR, Mamdani MM, Jiang D. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. Q J Med 2008;101:475–477.
  • Allen LH. Impact of vitamin B-12 deficiency during lactation on maternal and infant health. Adv Exp Med Biol 2002;503:57–67.
  • 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.
  • Allen LH. Vitamin B12 metabolism and status during pregnancy, lactation and infancy. Adv Exp Med Biol 1994;352:173–186.
  • Karnaze DS, Carmel R. Low serum cobalamin levels in primary degenerative dementia. Do some patients harbor atypical cobalamin deficiency states? Arch Intern Med 1987;147:429–431.
  • Savage DG, Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol 1995;8:657–678.
  • Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995;45:1435–1440.
  • Afman LA, Van Der Put NMJ, Thomas CMG, Trijbels JMF, Blom HJl. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects. Q J Med 2001;94:159–166.
  • Ray JG, Blom HJ. Vitamin B12 insufficiency and the risk of fetal neural tube defects. Q J Med 2003;96:289–295.
  • Groenen PMW, van Rooij IALM, Peer PGM, Gooskens RH, Zielhuis GA, Steegers-Theunissen RPM. Marginal maternal vitamin B12 status increases the risk of offspring with spina bifida. Am J Obstet Gynecol 2004;191:11–17.
  • Muthayya S, Kurpad AV, Duggan CP, Bosch RJ, Dwarkanath P, Mhaskar A, Mhaskar R, Thomas A, Vaz M, Bhat S, 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.
  • Ray JG, Wyatt PR, Thompson MD, Vermeulen MJ, Meier C, Wong PY, Farrell SA, Cole DE. Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population. Epidemiology 2007;18:362–366.
  • Schorah CJ, Smithells RW, Scott J. Vitamin B12 and anencephaly. Lancet 1980;1:880.
  • Suarez L, Hendricks K, Felkner M, Gunter E. Maternal serum B12 levels and risk for neural tube defects in a texas-mexico border population. Ann Epidemiol 2003;13:81–88.
  • Kirke PN, Molloy AM, Daly LE, Burke H, Weir DC, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med 1993;86:703–708.
  • Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC, Scott JM, Mills JL. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics 2009;123;917–923.
  • Thompson MD, Cole DE, Ray JG. Vitamin B12 and neural tube defects: the Canadian experience. Am Clin Nutr 2009;89:697s–701s.
  • Bjorke MAL, Ueland PM, Vollset SE, Guttormsen AB, Markestad T, Solheim E, Refsum H. Determinants of cobalamin status in newborns. Pediatrics 2001;108:624–630.
  • Jadhav M, Webb JK, Vaishnava S, Baker SJ. Vitamin B12 deficiency in Indian infants. A clinical syndrome. Lancet 1962;2:903–907.
  • Higginbottom MC, Sweetman L, Nyhan WL. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. N Engl J Med 1978;299:317–323.
  • 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.
  • Weiss R, Fogelman Y, Bennett M. Severe vitamin B12 deficiency in an infant associated with a maternal deficiency and a strict vegetarian diet. J Pediatr Hematol Oncol 2004;26:270–271.
  • Wighton MC, Manson JI, Speed I, Robertson E, Chapman E. Brain damage in infancy and dietary vitamin B12 deficiency. Med J Aust 1979;2:1–3.
  • Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 2008;29 (2 Suppl):S126–S131.
  • Lampkin BC, Saunders EF. Nutritional vitamin B12 deficiency in an infant. J Pediatr 1969;75:1053–1055.
  • Sklar R. Nutritional vitamin B12 deficiency in a breast-fed infant of a vegan-diet mother. Clin Pediatr (Phila) 1986;25:219–221.
  • Hellebostad M, Markestad T, Seeger Halvorsen K. Vitamin D deficiency rickets and vitamin B12 deficiency in vegetarian children. Acta Paediatr Scand 1985;74:191–195.
  • Gambon RC, Lentze MJ, Rossi E. Megaloblastic anaemia in one of monozygous twins breast fed by their vegetarian mother. Eur J Pediatr 1986;145:570–571.
  • Stollhoff K, Schulte FJ. Vitamin B12 and brain development. Eur J Pediatr 1987;146:201–205.
  • Kuhne T, Bubl R, Baumhartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr 1991;150:205–208.
  • Renault F, Verstichel P, Ploussard J-P, Costil J. Neuropathy in two cobalamin-deficient breast-fed infants of vegetarian mothers. Muscle Nerve 1999;22:252–254.
  • Shane B. Folate, vitamin B12 and vitamin B6. In: Stipanuk MH, Biochemical, physiological, molecular aspects of human nutrition, 2nd ed. editor. New York: Saunders; 2006. pp. 693–732.
  • Dakshinamurti S, Dakshinamurti KD. Vitamin B6. In: Zemplini J, Rucker DB, McCormick DB, Suttie JW, editors. Handbook of the vitamins. 4th ed. New York: CRC Press; 2007. pp. 315–360.
  • Coburn SP, Lewis DL, Fink WJ, Mahuren JD, Schaltenbrand WE, Costill DL. Human vitamin B6 pools estimated through muscle biopsies. Am J Clin Nutr 1988;48:291–294.
  • Gregory JF III. Bioavailability of vitamin B6. Eur J Clin Nutr 1997;51:S43–S48.
  • Nakano H, Gregory JF III. Pyridoxine and pyridoxine-5′-beta-d-glucoside exert different effects on tissue B-6 vitamins but similar effects of beta-glucosidase activity in rats. J Nutr 1997;125:2751–2762.
  • Institute of Medicine. Vitamin B6. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998, pp. 150–195.
  • Lumeng L, Ryan MP, Li TK. Validation of the diagnostic value of plasma pyridoxal 5′-phosphate measurements in vitamin B6 nutrition of the rat. J Nutr 1978;108:545–553.
  • Li A, Lumeng L, Aronoff GR, Li T-K. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans. J Lab Clin Med 1985;106:491–497.
  • Leklem JE. Vitamin B-6: a status report. J Nutr 1990;120:1503–1507.
  • Contractor SF, Shane B. Estimation of vitamin B6 compounds in human blood and urine. Clin Chim Acta 1968;21:71–77.
  • Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 1993;270:2693–2698.
  • WHO/FAO Thiamine, riboflavin, nioacin, vitamin B6, pantothenic acid, and biotin. Vitamin and mineral requirements in human nutrition. 2nd ed. Report of a joint FAO/WHO expert consultation, Bangkok, Thailand, 21–30 September 1998, 2004. pp. 164–193.
  • Mueller JF, Vilter RW. Pyridoxine deficiency in human beings induced by desoxypyridoxine. J Clin Invest 1950;29:193–201.
  • Snyderman SE, Holt LE, Carretero R, Jacobs K. Pyridoxine deficiency in the human infant. Am J Clin Nutr 1953;1:200.
  • Bessey OA, Adam DJ, Hansen AE. Intake of vitamin B6 and infantile convulsions: a first approximation of requirements of pyridoxine in infants. Pediatrics 1957;20:33–44.
  • Hawkins WW, Barsky J. An experiment on human vitamin B6 deprivation. Science 1948;108:284–286.
  • Coursin DB. Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc 1954;154:406–408.
  • Canham JE, Nunes WT, Eberlin EW. Electroencephalographic and central nervous system manifestations of vitamin B6 deficiency and induced vitamin B6 dependency in normal human adults. Proceedings of the sixth international congress on nutrition. Edinburgh: E & S Livingstone; 1964.
  • Kretsch MJ, Sauberlich HE, Newbrun E. Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women. Am J Clin Nutr 1991;53:1266–1274.
  • Hamfelt A, Tuvemo T. Pyridoxal phosphate and folic acid concentration in blood and erythrocyte aspartate aminotransferase activity during pregnancy. Clin Chim Acta 1972;41:287–298.
  • Cleary RE, Lumeng L, Li TK. Maternal and fetal plasma levels of pyridoxal phosphate at term: Adequacy of vitamin B6 supplementation during pregnancy. Am J Obstet Gynecol 1975;121:25–28.
  • Shane B, Contractor SF. Assessment of vitamin B 6 status. Studies on pregnant women and oral contraceptive users. Am J Clin Nutr 1975;28:739–747.
  • Shane B, Contractor SF. Vitamin B6 status and metabolism in pregnancy. In: Tryfiates GP, ed. Vitamin B6 metabolism and role in growth. Westport, CT: Food & Nutrition Press; 1980. pp. 137–171.
  • Contractor SF, Shane B. Blood and urine levels of vitamin B6 in the mother and fetus before and after loading of the mother with vitamin B6. Am J Obstet Gynecol 1970;15; 107: 635–640.
  • Barnard HC, de Kock JJ, Vermaak WJ, Potgieter GM. A new perspective in the assessment of vitamin B6 nutritional status during pregnancy in humans. J Nutr 1987;117:1303–1306.
  • Lumeng L, Cleary RE, Wagner R, Pao-Lo Y, Li TK. Adequacy of vitamin B6 supplementation during pregnancy: a prospective study. Am J Clin Nutr 1976;29:1376–1383.
  • Schuster K, Bailey LB, Mahan CS. Vitamin B6 status of low-income adolescent and adult pregnant women and the condition of their infants at birth. Am J Clin Nutr 1981;34:1731–1735.
  • Schuster K, Bailey LB, Mahan CS. Effect of maternal pyridoxine X HCl supplementation on the vitamin B-6 status of mother and infant and on pregnancy outcome. J Nutr 1984;114:977–988.
  • Thaver D, Saeed MA, Bhutta ZA. Pyridoxine (vitamin B6) supplementation in pregnancy. Cochrane Database Syst Rev 2006;2: CD000179.
  • Klieger JA, Evrard JR, Pierce R. Abnormal pyridoxine metabolism in toxemia of pregnancy. Am J Obstet Gynecol 1966;94:316–321.
  • Wachstein M. Evidence for abnormal vitamin B6 metabolism in pregnancy and various disease states. Am J Clin Nutr 1956;4:369–373.
  • Hillman RW, Cabaud PG, Schenore RA. The effects of pyridoxine supplements on the dental caries experience of pregnant women. Am J Clin Nutr 1962;10:512–515.
  • Hillman RW, Cabaud PG, Nilsson DE, Arpin PD, Tufano RJ. Pyridoxine supplementation during pregnancy. Clinical and laboratory observations. Am J Clin Nutr 1963;12:427–430.
  • Swartwout JR, Unglaub WG, Smith RC. Vitamin B6, serum lipids and placental arteriolar lesions in human pregnancy. Am J Clin Nutr 1960;8:434–444.
  • Brophy MH, Siiteri PK. Pyridoxal phosphate and hypertensive disorders of pregnancy. Am J Obstet Gynecol 1975;121:1075–1079.
  • Gaynor R, Dempsey WB. Vitamin B 6 enzymes in normal and pre-eclamptic human placentae. Clin Chim Acta 1972 37:411–416.
  • Weinstein BB, Wohl Z, Mitchell GJ, Sustendal GF. Oral administration of pyridoxine hydrochloride in the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol 1944;47:389–394.
  • Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of the premenstrual syndrome – a review. Br J Obstet Gynaecol 1990;97:847–852.
  • Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ 1999;318:1375–1381.
  • Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol 1991;78:33–36.
  • Schuster K, Bailey LB, Dimperio D, Mahan CS. Morning sickness and vitamin B6 status of pregnant women. Hum Nutr Clin Nutr 1985;39:75–79.
  • Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2002;1: CD000145.
  • Davis SD, Nelson T, Shepard TH. Teratogenicity of vitamin B6 deficiency: omphalocele, skeletal and neural defects, and splenic hypoplasia. Science 1970;169:1329–1330.
  • Aycock, JE, Kirksey A. Influence of different levels of dietary pyridoxine on certain parameters of developing and mature brains in rats. J Nutr 1976;106:680–688.
  • Cohen M, Bendich A. Safety of pyridoxine – a review of human and animal studies. Toxicol Lett 1986;34:129–139.
  • Schaumburg HH, Berger A. Pyridoxine neurotoxicity. In: Leklem JE, Reynolds RD, editors. Clinical and physiological applications of vitamin B6. New York: Alan R. Liss; 1988. pp. 403–414.
  • Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. Sensory neuropathy from pyridoxine abuse. N Engl J Med 1983;309:445–448.
  • Foukas MD. An antilactogenic effect of pyridoxine. J Obstet Gynaecol Br Commonw 1973;80:718–720.
  • Marcus RG. Suppression of lactation with high doses of pyridoxine. S Afr Med J 1975;49:2155–2156.
  • Scaglione D, Vecchione A. Pyridoxine for the suppression of lactation – a clinical trial on 1592 cases. Acta Vitaminol Enzymol 1982;4:207–214.
  • Donaldson GL, Bury RG. Multiple congenital abnormalities in a newborn boy associated with maternal use of fluphenazine enanthate and other drugs during pregnancy. Acta Paediatr Scand 1982;71:335–338.
  • Gardner LI, Welsh-Sloan J, Cady RB. Phocomelia in infant whose mother took large doses of pyridoxine during pregnancy. Lancet 1985;1:636.
  • Philpot J, Muntoni F, Skellett S, Dubowitz V. Congenital symmetrical weakness of the upper limbs resembling brachial plexus palsy: a possible sequel of drug toxicity in the first trimester of pregnancy. Neuromuscul Disord 1995;5:67–69.
  • Shrim A, Boskovic R, Maltepe C, Navios Y, Garcia-Bournissen F, Koren G. Pregnancy outcome following use of large doses of vitamin B6 in the first trimester. J Obstet Gynaecol 2006;26:749–751.
  • Czeizel AE, Puho E, Banhidy F, Acs N. Oral pyridoxine during pregnancy: potential protective effect for cardiovascular malformations. Drugs RD 2004;5:259–269.
  • Schumacher MF, Williams MA, Lyman RL. Effect of high intakes of thiamine, riboflavin and pyridoxine on reproduction in rats and vitamin requirements of the offspring. J Nutr 1965;86:343–349.
  • Khera KS. Teratogenicity study in rats given high doses pyridoxine (vitamin B6) during organogenesis. Experientia 1975;31:469–470.
  • Brent RL. Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 1995;9:337–349.
  • McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth defects. I. A meta-analysis of the epidemiologic studies. Teratology 1994;50:27–37.
  • MacMahon B. More on bendectin. J Am Med Assoc 1981;246:371–372.
  • Cordero JF, Oakley GP Jr.. Drug exposure during pregnancy: some epidemiologic considerations. Clin Obstet Gynecol 1983;26:418–428.
  • Neutel CI, Johansen HL. Measuring drug effectiveness by default: the case of Bendectin. Can J Public Health 1995;86:66–70.

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