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Effects and safety of periconceptional folate supplementation for preventing birth defects

  1. Luz Maria De-Regil1,*,
  2. Ana C Fernández-Gaxiola2,
  3. Therese Dowswell3,
  4. Juan Pablo Peña-Rosas1

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 6 OCT 2010

Assessed as up-to-date: 10 AUG 2010

DOI: 10.1002/14651858.CD007950.pub2

How to Cite

De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD007950. DOI: 10.1002/14651858.CD007950.pub2.

Author Information

  1. 1

    World Health Organization, Micronutrients Unit, Department of Nutrition for Health and Development, Geneva, Geneva, Switzerland

  2. 2

    Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico

  3. 3

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, Liverpool, UK

*Luz Maria De-Regil, Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva, Geneva, 1211, Switzerland. deregillu@who.int.

Publication History

  1. Publication Status: New
  2. Published Online: 6 OCT 2010

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References

References to studies included in this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to ongoing studies
  4. Additional references
Czeizel 1994 {published data only}
ICMR 2000 {published data only}
  • Indian Council of Medical Research (ICMR) Collaborating Centres, Central Technical Co-ordinating Unit. Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India. Indian Journal of Medical Research 2000;112:206-11.
Kirke 1992 {published data only}
Laurence 1981 {published data only}
  • Laurence KM. Prevention of neural tube defects by improvement in maternal diet and preconceptional folic acid supplementation. Progress in Clinical and Biological Research 1985;163:383-8.
  • Laurence KM. The role of maternal nutrition and folic acid therapy before conception to prevent neural tube defects [Die Rolle der mütterlichen Ernährung und Folinsaure-Therapie vor der Empfangnis zur Verhutung von Nervenkanal-Defekten]. Monatsschrift fur Kinderheilkunde 1982;130:646.
  • Laurence KM, Campbell H, James NE. The role of improvement in the maternal diet and preconceptional folic acid supplementation in the prevention of neural tube defects. Prevention of spina bifida and other neural tube defects. Academic Press, 1983:85-125.
  • Laurence KM, James N, Miller M, Campbell H, Tennant GB. A double randomised controlled trial for preconceptional folic acid supplementation for the prevention of recurrence of neural tube defects in high risk pregnancies. Journal of Medical Genetics 1982;19(1):66.
  • Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. BMJ (Clinical Research Edition) 1981;282:1509-11.
MRC 1991 {published data only}
  • Anon. Folate supplements prevent recurrence of neural tube defects. Nutrition Review 1992;50(Suppl 1):22-4.
  • Anon. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338(8760):131-7.

References to studies excluded from this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to ongoing studies
  4. Additional references
Atukorala 1994 {published data only}
  • Atukorala TM, de Silva LD, Dechering WH, Dassenaeike TS, Perera RS. Evaluation of effectiveness of iron-folate supplementation and anthelminthic therapy against anemia in pregnancy - a study in the plantation sector of Sri Lanka. American Journal of Clinical Nutrition 1994;60(2):286-92.
Bailey 2005 {published data only}
  • Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. American Journal of Clinical Nutrition 2005;81(5):1213S-17S.
Binns 2006 {published data only}
  • Binns C, Scott J, Nwafor N, Graham K, Oddy W, Lee A, et al. Which mothers take folic acid and folate containing foods?. Asia Pacific Journal of Clinical Nutrition 2006;15(3):335-40.
  • Oddy WH, Miller M, Payne JM, Serna P, Bower CI. Awareness and consumption of folate-fortified foods by women of childbearing age in Western Australia. Public Health Nutrition 2007;10(10):989-95.
Botto 2006 {published data only}
Canfield 2005 {published data only}
  • Canfield MA, Collins JS, Botto LD, Williams LJ, Mai CT, Kirby RS, et al. 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. Birth Defects Research 2005;73(10):679-89.
Chen 2008 {published data only}
Christian 2003 {published data only}
  • Christian P. Personal communication 28 September 2007.
  • Christian P, Darmstadt GL, Wu L, Khatry SK, LeClerq SC, Katz J, et al. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomised, controlled, community trial. Archives of Disease in Childhood 2008;93(8):660-4.
  • Christian P, Jiang T, Khatry SK, LeClerq SC, Shrestha SR, West Jr KP. Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. American Journal of Clinical Nutrition 2006;83:788-74.
  • Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, et al. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ 2003;326(7389):571.
  • Christian P, Khatry SK, LeClerq SC, Dali SM. Effects of prenatal micronutrient supplementation on complications of labor and delivery and puerperal morbidity in rural Nepal. International Journal of Gynecology & Obstetrics 2009;106(1):3-7.
  • Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T, Wagner T, et al. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. Journal of Nutrition 2003;133(11):3492-8.
  • Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP Jr, et al. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. American Journal of Epidemiology 2009;170(9):1127-36.
  • Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP Jr, et al. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. American Journal of Epidemiology 2009;170(9):1127-36.
  • Christian P, West KP, Khatry SK, Leclerq SC, Pradhan EK, Katz J, et al. Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. American Journal of Clinical Nutrition 2003;78(6):1194-202.
  • Christian PS, Darmstadt GL, Wu L, Khatry SK, Leclerq SC, Katz J, et al. The impact of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomized, controlled, community trial. Archives of Disease in Childhood. Fetal and Neonatal Edition 2007; Vol. [Epub ahead of print].
  • Katz J, Christian P, Dominici F, Zeger SL. Treatment effects of maternal micronutrient supplementation vary by percentiles of the birth weight distribution in rural Nepal. Journal of Nutrition 2006;136(5):1389-94.
  • Kulkarni B, Christian P, LeClerq SC, Khatry SK. Determinants of compliance to antenatal micronutrient supplementation and women's perceptions of supplement use in rural Nepal. Public Health Nutrition 2010;13(1):82-90.
  • Stewart CP, Christian P, LeClerq SC, West KP Jr, Khatry SK. Antenatal supplementation with folic acid + iron + zinc improves linear growth and reduces peripheral adiposity in school-age children in rural Nepal. American Journal of Clinical Nutrition 2009;90(1):132-40.
  • Stewart CP, Christian P, Schulze KJ, Leclerq SC, West KP Jr, Khatry SK. Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal. Journal of Nutrition 2009;139(8):1575-81.
  • Stewart CP, Katz J, Khatry SK, LeClerq SC, Shrestha SR, West KP Jr, et al. Preterm delivery but not intrauterine growth retardation is associated with young maternal age among primiparae in rural Nepal. Maternal & Child Nutrition 2007;3(3):174-85.
Daly 1995 {published data only}
  • Daly SF, Cahill E, Turner MJ. Can fortified milk raise folic acid levels in non pregnant women?. 27th British Congress of Obstetrics and Gynaecology; 1995 July 4-7, Dublin, Ireland. 1995:Abstract no: 456.
Daly 1997 {published data only}
  • Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, et al. Minimum effective dose of folic acid for food fortification to prevent neural tube defects. Lancet 1997;350:1666-9.
  • Daly S, Mills JL, Molloy AM, Conley M, McPartlin J, Lee YJ, Young PB, Kirke PN, Weir DG, Scott JM. Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age. QJM 2002;95(11):733-40.
Doyle 2001 {published data only}
  • Doyle W, Srivastava A, Crawford MA, Bhatti R, Brooke Z, Costeloe KL. Inter-pregnancy folate and iron status of women in an inner-city population. British Journal of Nutrition 2001;86(1):81-7.
Drazkowski 2002 {published data only}
Eichholzer 2006 {published data only}
Ejidokun 2000 {published data only}
Elbourne 2002 {published data only}
Ellison 2004 {published data only}
Eskes 2000 {published data only}
  • Eskes TK. Homocysteine and human reproduction. Clinical and Experimental Obstetrics and Gynecology 2000;27(3-4):157-67.
Field 1991 {published data only}
  • Field B. Neural tube defects. The role of vitamin supplementation in their prevention. Current Therapeutics 1991;32(3):11-3.
Geisel 2003 {published data only}
Hague 2003 {published data only}
Hayes 1996 {published data only}
Itikala 2001 {published data only}
Johnston 2008 {published data only}
  • Johnston RB Jr. Will increasing folic acid in fortified grain products further reduce neural tube defects without causing harm? Consideration of the evidence. Pediatric Research 2008;63(1):2-8.
Khambalia 2009 {published data only}
  • Khambalia AZ, O'Connor DL, Macarthur C, Dupuis A, Zlotkin SH. Periconceptional iron supplementation does not reduce anemia or improve iron status among pregnant women in rural Bangladesh. American Journal of Clinical Nutrition 2009;90(5):1295-302.
Lee 2005 {published data only}
  • Lee JI, Lee JA, Lim HS. Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy. American Journal of Clinical Nutrition 2005;82(4):843-9.
Mandishona 1999 {published data only}
  • Mandishona EM, Moyo VM, Gordeuk VR, Khumalo H, Saungweme T, Gangaidzo IT, et al. A traditional beverage prevents iron deficiency in African women of child bearing age. European Journal of Clinical Nutrition 1999;53(9):722-5.
Manizheh 2009 {published data only}
  • Manizheh SM, Mandana S, Hassan A, Amir GH, Mahlisha KS, Morteza G. Comparison study on the effect of prenatal administration of high dose and low dose folic acid. Saudi Medical Journal 2009;30(1):88-97.
Mathews 1999 {published data only}
Melli 2008 {published data only}
  • Melli MS, Shojaiee M, Sheshvan MK. Prenatal administration of high dose and low dose folic acid on maternal plasma homocysteine concentration and its relationship to the development of preeclampsia. Journal of Maternal-Fetal and Neonatal Medicine 2008;21(Suppl 1):82.
Molster 2007 {published data only}
Nelen 2000 {published data only}
  • Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstetrics & Gynecology 2000;95(4):519-24.
Nguyen 2009 {published data only}
  • Nguyen P, Tam C, O'Connor DL, Kapur B, Koren G. Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age. American Journal of Clinical Nutrition 2009;89:844-52.
Pitkin 2007 {published data only}
Pritchard 1991 {published data only}
  • Pritchard JA, Cunningham FG, Pritchard SA, Mason RA. On reducing the frequency of severe abruptio placentae. American Journal of Obstetrics & Gynecology 1991;165(5 Pt 1):1345-51.
Ramakrishnan 2003 {published data only}
  • Garcia-Guerra A, Neufeld LM, Hernandez-Cordero S, Rivera J, Martorell R, Ramakrishnan U. Prenatal multiple micronutrient supplementation impact on biochemical indicators during pregnancy and postpartum. Salud Publica de Mexico 2009;51(4):327-35.
  • Ramakrishnan U, Gonzalez-Cossio T, Neufeld LM, Rivera J, Martorell R. Multiple micronutrient supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation: a randomised controlled trial in a semirural community in Mexico. American Journal of Clinical Nutrition 2003;77(3):720-5.
  • Ramakrishnan U, Gonzalez-Cossio T, Neufeld L M, Rivera J, Martorell R. Effect of prenatal multiple micronutrient supplements on maternal weight and skinfold changes: a randomized double-blind clinical trial in Mexico. Food & Nutrition Bulletin 2005;26(3):273-80.
  • Ramakrishnan U, Neufeld LM, Gonzalez-Cossio T, Villalpando S, Garcia-Guerra A, Rivera J, et al. Multiple micronutrient supplements during pregnancy do not reduce anemia or improve iron status compared to iron-only supplements in semirural Mexico. Journal of Nutrition 2004;134(4):898-903.
Ray 2007 {published data only}
  • 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(3):362-6.
Ray 2008 {published data only}
  • Ray JG, Goodman J, O'Mahoney PR, Mamdani MM, Jiang D, O'Mahoney PRA. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. Qjm 2008;101(6):475-7.
Robbins 2005 {published data only}
  • Robbins JM, Cleves MA, Collins HB, Andrews N, Smith LN, Hobbs CA, et al. Randomized trial of a physician-based intervention to increase the use of folic acid supplements among women. American Journal of Obstetrics & Gynecology 2005;192(4):1126-32.
  • Robbins JM, Hopkins SE, Mosley BS, Casey PH, Cleves MA, Hobbs CA, et al. Awareness and use of folic acid among women in the lower Mississippi Delta. Journal of Rural Health 2006;22(3):196-203.
  • Robbins J M, Tilford JM, Bird TM, Cleves MA, Reading JA, Hobbs CA, et al. Hospitalizations of newborns with folate-sensitive birth defects before and after fortification of foods with folic acid [erratum appears in Pediatrics. 2006 Dec;118(6):2608]. Pediatrics 2006;118(3):906-15.
Rolschau 1999 {published data only}
  • Rolschau J, Kristoffersen K, Ulrich M, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I. European Journal of Obstetric & Gynecology and Reproductive Biology 1999;87(2):105-10; discussion 103-4.
  • Ulrich M, Kristoffersen K, Rolschau J, Grinstead P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part II. Congenital anomalies A randomised study. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87:111-3.
  • Ulrich M, Kristoffersen K, Rolschau J, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part III. Congenital anomalies. An observational study. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87(2):115-8; discussion 103-4.
Sayers 1997 {published data only}
Schorah 1993 {published data only}
Schwarz 2008 {published data only}
  • Schwarz EB, Sobota M, Gonzales R, Gerbert B. Computerized counseling for folate knowledge and use: a randomized controlled trial. American Journal of Preventive Medicine 2008;35(6):568-71.
Shaw 1995 {published data only}
  • Shaw GM, Lammer EJ, Wasserman CR, O'Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;346(8972):393-6.
Shaw 2006 {published data only}
Shrimpton 2002 {published data only}
van der Put 1998a {published data only}
  • van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. American Journal of Human Genetics 1998;62(5):1044-51.
van Rooij 2004 {published data only}
  • van Rooij IA, Ocke MC, Straatman H, Zielhuis GA, Merkus HM, Steegers-Theunissen RP, et al. Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate. Preventive Medicine 2004;39(4):689-94.
Wald 2004 {published data only}
Walsh 2007 {published data only}
  • Walsh T, O'Broin S, Cooley S, Donnelly J, Collins C, McMillan H, et al. Maternal folate status and neural tube defects in Ireland: the need for a national food fortification program. Irish Medical Journal 2007;100(5):469-72.
Watson 1999 {published data only}
  • Watson LF, Watson MJ, Halliday JL, Bell RJ. Consequences of surveying folate awareness. Health Expectations 2002;5(1):38-46.
  • Watson LW. The epidemiology of folate and neural tube defects: a community intervention and ongoing issues. Australasian Epidemiologist 2003;10:6-8.
  • Watson M, Watson L, Bell R, Halliday J. The increasing knowledge of the role of periconceptional folate in Victorian women of child-bearing age: follow-up of a randomised community intervention trial. Australian & New Zealand Journal of Public Health 2001;25(5):389-95.
  • Watson M, Watson L, Bell R, Halliday J, Burford N, Brennecke S. Increasing knowledge of the role of folate in women of child-bearing age in Victoria - a randomised trial. 2nd Annual Congress of the Perinatal Society of Australia & New Zealand; 1998 March 30-April 4; Alice Springs, Australia. 1998:114.
  • Watson MJ, Watson LF, Bell RJ, Halliday JL, Burford N, Brennecke SP. A randomized community intervention trial to increase awareness and knowledge of the role of periconceptional folate in women of child-bearing age. Health Expectations 1999;2:255-65.
Wen 2005 {published data only}
  • Wen SW, Walker M. An exploration of health effects of folic acid in pregnancy beyond reducing neural tube defects. Journal of Obstetrics & Gynaecology Canada: JOGC 2005;27(1):13-9.
Westphal 2004 {published data only}
  • Westphal LM, Polan ML, Trant AS. Double-blind, placebo-controlled study of FertilityBlend: a nutritional supplement for improving fertility in women. Clinical and Experimental Obstetrics and Gynecology 2006;33(4):205-8.
  • Westphal LM, Polan ML, Trant AS, Mooney SB. A nutritional supplement for improving fertility in women: a pilot study. Journal of Reproductive Medicine 2004;49(4):289-93.
Wilcox 2007 {published data only}
  • Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 2007;334(7591):464.
Zeng 2008 {published data only}
  • Li Q, Yan H, Zeng L, Cheng Y, Liang W, Dang S, et al. Effects of maternal multimicronutrient supplementation on the mental development of infants in rural western China: follow-up evaluation of a double-blind, randomized, controlled trial. Pediatrics 2009;123(4):e685-92.
  • Zeng L, Dibley MJ, Cheng Y, Dang S, Chang S, Kong L, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial. BMJ 2008;337:a2001.

References to ongoing studies

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to ongoing studies
  4. Additional references
Javois 2006 {published data only}
  • Javois L. Birth defects treatment and prevention program: oral cleft prevention program (ongoing trial). ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 21 March 2006).

Additional references

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to ongoing studies
  4. Additional references
Berry 1999
  • Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. collaborative project for neural tube defect prevention. New England Journal of Medicine 1999;341(20):1485-90.
Berry 2004
  • Berry RJ, Kihlberg R, Devine D. Impact of misclassification of in vitro fertilisation in studies of folic acid and twinning: modelling using population based Swedish vital records. BMJ 2004;330:815.
Berry 2010
  • Berry RJ, Bailey L, Mulinare J, Bower C. Folic Acid Working Group. Fortification of flour with folic acid. Food Nutrition Bulletin 2010;31(Suppl 1):S22-35.
Botto 2006
Botto 2000
Botto 2004
Botto 2005
  • Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE, Mastroiacovo P, et al. International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?. BMJ 2005;330:571-3.
Brandalize 2009
Carter 2005
  • Carter JY, Loolpapit MP, Lema OE, Tome JL, Nagelkerke NJ, Watkins WM. Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation. American Journal of Tropical Medicine and Hygiene 2005;73(1):166-70.
CDC 1992
  • US Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Morbidity and Mortality Weekly Report 1992;41((RR-14)):1-7.
CDC 2008a
  • Centers for Disease Control and Prevention. National Report on Biochemical Indicators of Diet and Nutrition in the US Population 1999-2002. Water soluble vitamins and related biochemical compounds. Atlanta, GA: Department of Health and Human Services, 2008.
CDC 2008b
  • Centers for Disease Control and Prevention (CDC). Trends in wheat-flour fortification with folic acid and iron - worldwide, 2004 and 2007. MMWR. Morbidity and Mortality Weekly Report 2008;57(1):8-10.
Chango 2000
  • Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS, et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Molecular Genetics and Metabolism 2000;70(4):310-5.
Cole 2007
Coppede 2009
Czeizel 1992
Czeizel 1999b
Czeizel 2004
  • Czeizel AE. The primary prevention of birth defects: multivitamins or folic acid?. International Journal of Medical Sciences 2004;1(1):50-61.
Daly 1997
Dary 2009
De Wals 2007
  • De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Dibbald B, et al. Reduction in neural-tube defects after folic acid fortification in Canada. New England Journal of Medicine 2007;357(2):135-42.
Elsinga 2006
  • Elsinga J, van der Pal-de Bruin K, le Cessie S, de Jong-Potjer L, Verloove-Vanhorick S, Assendelft W. Preconception counselling initiated by general practitioners in the Netherlands: reaching couples contemplating pregnancy [ISRCTN53942912]. BMC Family Practice 2006;7:41.
English 2006
Eskes 2006
  • Eskes TK. Abnormal folate metabolism in mothers with Down syndrome offspring: review of the literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2006;124(2):130-3.
Fazili 2007
  • Fazili Z, Pfeiffer CM, Zhang M. Comparison of serum folate species analyzed by LC-MS/MS with total folate measured by microbiologic assay and Bio-Rad radioassay. Clinical Chemistry 2007;53:781-4.
Fife 2009
  • Fife J, Raniga S, Hider PN, Frizelle FA. Folic acid supplementation and colorectal cancer risk; a meta-analysis. Colorectal Disease 2009;Oct 27:Epub ahead of print.
Glasier 2006
Goh 2006
  • Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. Journal of Obstetrics and Gynaecology Canada: JOGC 2006;28:680-9.
Goh 2007
Guéant-Rodriguez 2006
  • Guéant-Rodriguez RM, Guéant JL, Debard R, Thirion S, Hong LX, Bronowicki JP, et al. Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations. American Journal of Clinical Nutrition 2006;83(3):701-7.
Haider 2006
Haider 2008
  • Haider BA, Humayun Q, Bhutta ZA, Jabeen A. Folate supplementation in pregnancy. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/14651858.CD006896.]
Higgins 2008
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
Houghton 2006
  • Houghton LA, Sherwood KL, Pawlosky R, Ito S, O'Connor DL. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. American Journal of Clinical Nutrition 2006;83(4):842-50.
IOM 1998
  • Institute of Medicine. Folate. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press, 1998:196-303.
IOM 2003
  • Bale JR, Stoll BJ, Lucas AO, editors. Reducing birth defects: meeting the challenge in the developing world. Washington: National Academies Press, 2003.
Iyengar 1975
Jaszewski 2008
  • Jaszewski R, Misra S, Tobi M, Ullah N, Naumoff JA, Kucuk O, et al. Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World Journal Gastroenterology 2008;28(14):4492-8.
Lamers 2004
  • 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. American Journal of Clinical Nutrition 2004;79(3):473-8.
Life Sciences Research Office 1994
  • Life Sciences Research Office, Center for Food Safety and Applied Nutrition. Assessment of folate methodology used in the Third National Health and Nutrition Survey (NHANES 1988-1994). Washington DC: U.S. Food and Drug Administration, Department of Health and Human Services, 1994.
Lumley 2001
  • Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database of Systematic Reviews 2001, Issue 3. [DOI: 10.1002/14651858.CD001056]
Makedos 2007
  • Makedos G, Papanicolaou A, Hitoglou A, Kalogiannidis I, Makedos A, Vrazioti V, et al. Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia. Archives of Gynecology & Obstetrics 2007;275(2):121-4.
Marinho 2009
  • Marinho C, Alho I, Guerra A, Rego C, Areias J, Bicho M. The methylenetetrahydrofolate reductase gene variant (C677T) as a susceptibility gene for tetralogy of Fallot. Revista Portuguesa de Cardiologia 2009;28(7-8):809-12.
Martinez-de Villareal 2001
  • Martinez-de Villareal L, Limón-Benavides C, Valdez-Leal R, Sánchez-Peña MA, Villareal-Pérez JZ. Impact of weekly administration of folic acid on folic acid blood levels. Salud Publica de Mexico 2001;43(2):103-7.
Martinez-de Villareal 2002
Mason 2007
  • Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiology, Biomarkers & Prevention 2007;16(7):1325-9.
McNulty 2004
Modell 1989
MRC 1991
  • Anonymous. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338(8760):131-7.
Murray 1997
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