Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 μg and 400 μg per Day
Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥ 906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 μg/day and 140 μg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 μg ( n = 49), 400 μg ( n = 48) or placebo ( n = 47) for 40？weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40？weeks. At 40 weeks, the overall prevalence of having a RBC folate < 906 nmol/L decreased to 18% and 35% in the 400 μg and 140 μg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups ( P = 0.340), nor was there evidence of a difference in the odds of a RBC folate < 906 nmol/L ( P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.
References
[1]
Department of Health Scottish Office Home and Health Department, Welsh Office, Department of Health and Social Services, Northern Ireland. Report from an Expert Advisory Group on Folic Acid and the Prevention of Neural Tube Defects; Department of Health: London, UK, 1992.
[2]
Public Health Service, 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 Morb. Mortal. Wkly. Rep.？1992, 41, 1–7.
[3]
National Health and Medical Research Council. Revised Statement on the Relationship between Dietary Folic Acid and Neural Tube Defects Such As Spina Bifida; NHMRC: Melbourne, Australia, 1993.
[4]
Commission of the European Communities. Nutrient and Energy Intakes for the European Community; Reports of the Scientific Committee for Food Thirty-First Series; Office for Official Publications of the European Communities: Luxembourg, 1993.
[5]
Mulinare, J.; Cordero, J.F.; Erickson, J.D.; Berry, R.J. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA？1988, 260, 3141–3145.
[6]
Milunsky, A.; Jick, H.; Jick, S.S.; Bruell, C.L.; MacLaughlin, D.S.; Rothman, K.J.; Willett, W. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA？1989, 262, 2847–2852.
[7]
Werler, M.M.; Shapiro, S.; Mitchell, A.A. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA？1993, 269, 1257–1261.
[8]
Shaw, G.M.; Schaffer, D.; Velie, E.M.; Morland, K.; Harris, J.A. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology？1995, 6, 219–226.
[9]
Khoury, M.J.; Shaw, G.M.; Moore, C.A.; Lammer, E.J.; 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.
[10]
Berry, R.J.; Li, Z.; Erickson, J.D.; Li, S.; Moore, C.A.; Wang, H.; Mulinare, J.; Zhao, P.; Wong, L.Y.; Gindler, J.; Hong, S.X.; Correa, A. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N. Engl. J. Med.？1999, 341, 1485–1490. 10559448
Pfeiffer, C.M.; Johnson, C.L.; Jain, R.B.; Yetley, E.A.; Picciano, M.F.; Rader, J.I.; Fisher, K.D.; Mulinare, J.; Osterloh, J.D. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988–2004. Am. J. Clin. Nutr.？2007, 86, 718–727.
[13]
Honein, M.A.; Paulozzi, L.J.; Mathews, T.J.; Erickson, J.D.; Wong, L.Y.C. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA？2001, 285, 2981–2986.
[14]
Williams, L.J.; Mai, C.T.; Edmonds, L.D.; Shaw, G.M.; Kirby, R.S.; Hobbs, C.A.; Sever, L.E.; Miller, L.A.; Meaney, F.J.; Levitt, M. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology？2002, 66, 33–39.
[15]
De Wals, P.; Tairou, F.; Van Allen, M.I.; Uh, S.H.; Lowry, R.B.; Sibbald, B.; Evans, J.A.; Van den Hof, M.C.; Zimmer, P.; Crowley, M. Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada. N. Engl. J. Med.？2007, 357, 135–142.
[16]
De Wals, P.; Rusen, I.D.; Lee, N.S.; Morin, P.; Niyonsenga, T. Trend in prevalence of neural tube defects in Quebec. Clin. Mol. Teratol.？2003, 67, 919–923.
[17]
Ray, J.G.; Meier, C.; Vermeulen, M.J.; Boss, S.; Wyatt, P.R.; Cole, D.E. Association of neural tube defects and folic acid food fortification in Canada. Lancet？2002, 360, 2047–2048.
[18]
Persad, V.L.; van den Hof, M.C.; Dube, J.M.; Zimmer, P. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ？2002, 167, 241–245.
[19]
Liu, S.; West, R.; Randell, E.; Longerich, L.; O’Connor, K.S.; Scott, H.; Crowley, M.; Lam, A.; Prabhakaran, V.; McCourt, C. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth？2004, 4, 20.
[20]
Canfield, M.A.; Collins, J.S.; Botto, L.D.; Williams, L.J.; Mai, C.T.; Kirby, R.S.; Pearson, K.; Devine, O.; Mulinare, J. Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Clin. Mol. Teratol.？2005, 73, 679–689.
[21]
Proposed Amendment to the New Zealand Folic Acid Standard; NZFSA Public Discussion Paper No. 10/09; New Zealand Food Safety Authority: Wellington, New Zealand, 2009.
[22]
Australian New Zealand Clinical Trials Registry. Effect of mandatory folic acid fortification policy on folate status of New Zealand women of childbearing age. ACTRN12609000215224. Available online: http://www.anzctr.org.au/trial_view.aspx?ID=83422 (accessed on 4 December 2008).
[23]
Lohman, T.J.; Roche, A.F.; Martorell, R. Anthropometric Standardization Reference Manual; Human Kinetics Publications: Champaign, IL, USA, 1988.
[24]
New Zealand Food Composition Database (FOODfiles); New Zealand Institute for Crop & Food Research Limited and Ministry of Health: Christchurch, New Zealand, 2006.
[25]
Molloy, A.M.; Scott, J.M. Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol.？1997, 281, 43–53.
[26]
Gibson, R.S. Principles of Nutritional Assessment, 2nd ed.; Oxford University Press: New York, NY, USA, 2005.
[27]
Venn, B.J.; Green, T.J.; Moser, R.; Mann, J.I. Comparison of the effect of low-dose supplementation with l-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am. J. Clin. Nutr.？2003, 77, 658–662.
[28]
Hao, L.; Yang, Q.H.; Li, Z.; Bailey, L.B.; Zhu, J.H.; Hu, D.J.; Zhang, B.L.; Erickson, J.D.; Zhang, L.; Gindler, J.; Li, S.; Berry, R.J. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am. J. Clin. Nutr.？2008, 88, 448–457.
[29]
Lamers, Y.; Prinz-Langenohl, R.; Moser, R.; Pietrzik, K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am. J. Clin. Nutr.？2004, 79, 473–478.
[30]
Molloy, A.M.; Brody, L.C.; Mills, J.L.; Scott, J.M.; Kirke, P.N. The search for genetic polymorphisms in the homocysteine/folate pathway that contribute to the etiology of human neural tube defects. Clin. Mol. Teratol.？2009, 85, 285–294.
[31]
Tighe, P.; Ward, M.; McNulty, H.; Finnegan, O.; Dunne, A.; Strain, J.; Molloy, A.M.; Duffy, M.; Pentieva, K.; Scott, J.M. A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy. Am. J. Clin. Nutr.？2011, 93, 11–18.
[32]
Bailey, R.L.; Dodd, K.W.; Gahche, J.J.; Dwyer, J.T.; McDowell, M.A.; Yetley, E.A.; Sempos, C.A.; Burt, V.L.; Radimer, K.L.; Picciano, M.F. Total folate and folic acid intakes from foods and dietary supplements in the United States: 2003–2006. Am. J. Clin. Nutr.？2010, 91, 231–237.
[33]
Shakur, Y.A.; Garriguet, D.; Corey, P.; O’Connor, D.L. Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians. Am. J. Clin. Nutr.？2010, 92, 818–825.
[34]
Bar-Oz, B.; Koren, G.; Nguyen, P.; Kapur, B.M. Folate fortification and supplementation—are we there yet? Reprod. Toxicol.？2008, 25, 408–412.
[35]
Nguyen, P.; Tam, C.; O’Connor, D.L.; Kapur, B.; Koren, G. Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age. Am. J. Clin. Nutr.？2009, 89, 844–852. 19158211
[36]
Heseker, H.B.; Mason, J.B.; Selhub, J.; Rosenberg, I.H.; Jacques, P.F. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. Br. J. Nutr.？2009, 102, 173–180.
[37]
Mosley, B.S.; Cleves, M.A.; Siega-Riz, A.M.; Shaw, G.M.; Canfield, M.A.; Waller, D.K.; Werler, M.M.; Hobbs, C.A. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am. J. Epidemiol.？2009, 169, 9–17.
[38]
Mills, J.L.; Carter, T.C. Invited commentary: Preventing neural tube defects and more via food fortification? Am. J. Epidemiol.？2009, 169, 18–21. 18953060
[39]
New Zealand Food Safety Authority. Folic Acid—Key Issues—NZFSA Response Science. Available online: http://www.nzfsa.govt.nz/consultation/folic-acid/nzfsa-response/folic-acid-key-issues-nzfsa-response.pdf (accessed on 22 October 2010).
[40]
New Zealand Ministry of Health. Nutrition—Folate/Folic Acid (Last updated 4 October 2010). 2010. Available online: http://www.moh.govt.nz/moh.nsf/indexmh/nutrition-folate#ntd2 (accessed on 22 October 2010).
[41]
Bower, C.; Klerk, N.; Hickling, S.; Ambrosini, G.; Flicker, L.; Geelhoed, E.; Milne, E. Assessment of the potential effect of incremental increases in folic acid intake on neural tube defects in Australia and New Zealand. Aust. N. Z. J. Public Health？2006, 30, 369–374.
[42]
Wald, N.J.; Law, M.R.; Morris, J.K.; Wald, D.S. Quantifying the effect of folic acid. Lancet？2001, 358, 2069–2073.
[43]
Ward, M.; McNulty, H.; McPartlin, J.; Strain, J.J.; Weir, D.G.; Scott, J.M. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM？1997, 90, 519–524.
[44]
Quinlivan, E.P.; Gregory, J.F., III. Effect of food fortification on folic acid intake in the United States. Am. J. Clin. Nutr.？2003, 77, 221–225.
[45]
Berry, R.J.; Bailey, L.; Mulinare, J.; Bower, C. Fortification of flour with folic acid. Food Nutr. Bull.？2010, 31, S22–S35.
[46]
Ministry of Health. Improving the Folate Intake in New Zealand: Policy Implications; Public Health Intelligence Occasional Bulletin Number 18; Ministry of Health: Wellington, New Zealand, 2003.
[47]
Schader, I.; Corwin, P. How many pregnant women in Christchurch are using folic acid supplements in early pregnancy? N. Z. Med. J.？1999, 112, 463–465. 10678210
[48]
Ferguson, E.L.; Skeaff, C.M.; Bourn, D.M. Folate Status of Representative Populations in Dunedin: Issues for Folate Fortification; A report prepared for the Ministry of Health and the Australian NZ Food Authority; University of Otago: Dunedin, New Zealand, 2000.
[49]
Dobson, I.; Devenish, C.; Skeaff, C.M.; Green, T.J. Periconceptional folic acid use among women giving birth at Queen Mary Maternity Hospital in Dunedin. Aust. N. Z. J. Obstet. Gynaecol.？2006, 46, 534–537.
