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Folic acid supplementation in pregnancy

Author
Laura M Goetzl, MD, MPH
Section Editor
Louise Wilkins-Haug, MD, PhD
Deputy Editor
Vanessa A Barss, MD, FACOG

INTRODUCTION

Periconceptional folic acid supplementation decreases the occurrence and recurrence of neural tube defects (NTDs). It is recommended for all women planning pregnancy or capable of becoming pregnant. Preconception patient education about the need for prophylaxis is important during medical wellness visits as many women are not aware of this recommendation until after they seek prenatal care or choose not to follow the recommendation because of cost or inconvenience [1,2]. Women who do not take supplements still consume some folic acid as folate is a natural component of a variety of foods, and grain products in many countries are fortified with folic acid.

This topic will discuss the role of folic acid supplementation for prevention of NTDs, dosing in women at average versus high risk of NTDs, potential benefits unrelated to NTDs, potential risks of supplementation, and NTDs that occur despite supplementation. Prenatal screening and diagnosis of NTDs are reviewed separately. (See "Open neural tube defects: Risk factors, prenatal screening and diagnosis, and pregnancy management".)

FOLATE AND FOLIC ACID

Although the terms folate and folic acid are often used interchangeably, folate is a water-soluble B vitamin (B9) that occurs naturally in foods, and folic acid is the synthetic form of folate.

Sources — Folate (B9) occurs naturally in several foods, including beef liver, leafy vegetables, peas and beans, avocados, eggs, and milk [3,4].

Folic acid is available in multivitamins, prenatal vitamins, and as a pure folic acid supplement. It is also added to fortify certain foods, including flour, pasta, breads, cereals, cornmeal, and rice, and it has been added to some oral estrogen-progestin contraceptive pills to ensure adequate baseline folate levels in the event of unplanned pregnancy from inconsistent/incorrect contraceptive use or conception soon after discontinuation.

                                  
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Literature review current through: Sep 2017. | This topic last updated: Oct 03, 2017.
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References
Top
  1. Youngblood ME, Williamson R, Bell KN, et al. 2012 Update on global prevention of folic acid-preventable spina bifida and anencephaly. Birth Defects Res A Clin Mol Teratol 2013; 97:658.
  2. Mills JL. Strategies for Preventing Folate-Related Neural Tube Defects: Supplements, Fortified Foods, or Both? JAMA 2017; 317:144.
  3. Sarmah S, Muralidharan P, Marrs JA. Common congenital anomalies: Environmental causes and prevention with folic acid containing multivitamins. Birth Defects Res C Embryo Today 2016; 108:274.
  4. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#h3 (Accessed on March 31, 2017).
  5. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010; 49:535.
  6. Daly LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. Implications for prevention. JAMA 1995; 274:1698.
  7. Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among U.S. women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med 2010; 38:534.
  8. Mosley BS, Cleves MA, Siega-Riz AM, et al. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am J Epidemiol 2009; 169:9.
  9. Ahrens K, Yazdy MM, Mitchell AA, Werler MM. Folic acid intake and spina bifida in the era of dietary folic acid fortification. Epidemiology 2011; 22:731.
  10. Atta CA, Fiest KM, Frolkis AD, et al. Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis. Am J Public Health 2016; 106:159.
  11. Castillo-Lancellotti C, Tur JA, Uauy R. Impact of folic acid fortification of flour on neural tube defects: a systematic review. Public Health Nutr 2013; 16:901.
  12. Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 1997; 350:1666.
  13. Viswanathan M, Treiman KA, Kish-Doto J, et al. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2017; 317:190.
  14. Folic acid supplementation for the prevention of neural tube defects. US Preventive Services Task Force recommendation statement. JAMA 2017; 317:183.
  15. Locksmith GJ, Duff P. Preventing neural tube defects: the importance of periconceptional folic acid supplements. Obstet Gynecol 1998; 91:1027.
  16. Gunter EW, Bowman BA, Caudill SP, et al. Results of an international round robin for serum and whole-blood folate. Clin Chem 1996; 42:1689.
  17. Centers for Disease Control and Prevention. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6415a5.htm?s_cid=mm6415a5_e (Accessed on April 24, 2015).
  18. World Health Organization. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. Geneva, Switzerland: World Health Organization, 2015. http://www.who.int/nutrition/publications/guidelines/optimalserum_rbc_womenrep_tubedefects/en (Accessed on January 08, 2017).
  19. Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol 2015; 103:517.
  20. De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, Rayco-Solon P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015; :CD007950.
  21. Atta CA, Fiest KM, Frolkis AD, et al. Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis. Am J Public Health 2016; 106:e24.
  22. Wilson RD, Genetics Committee, Wilson RD, et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can 2015; 37:534.
  23. Grosse SD, Collins JS. Folic acid supplementation and neural tube defect recurrence prevention. Birth Defects Res A Clin Mol Teratol 2007; 79:737.
  24. Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006; 28:680.
  25. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327:1832.
  26. National Institute for Health and Care Excellence. Maternal and child nutrition, 2008. https://www.nice.org.uk/guidance/ph11/chapter/4-Recommendations#folic-acid-2 (Accessed on August 18, 2016).
  27. Toriello HV, Policy and Practice Guideline Committee of the American College of Medical Genetics. Policy statement on folic acid and neural tube defects. Genet Med 2011; 13:593.
  28. Finer LB, Zolna MR. Declines in Unintended Pregnancy in the United States, 2008-2011. N Engl J Med 2016; 374:843.
  29. Institute of Medicine, Food and Nutrition Board, Committee on Nutritional Status During Pregnancy. Part II: Dietary intake and nutrient supplements. In: Nutrition During Pregnancy, National Academies Press, Washington, DC 1990.
  30. Patel KR, Sobczyńska-Malefora A. The adverse effects of an excessive folic acid intake. Eur J Clin Nutr 2017; 71:159.
  31. Arth A, Tinker S, Moore C, et al. Supplement use and other characteristics among pregnant women with a previous pregnancy affected by a neural tube defect - United States, 1997-2009. MMWR Morb Mortal Wkly Rep 2015; 64:6.
  32. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991; 338:131.
  33. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet 2001; 358:2069.
  34. Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004; 350:101.
  35. Biale Y, Lewenthal H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 1984; 18:211.
  36. Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009; 73:142.
  37. American College of Obstetricians and Gynecologists. Preconception and interconception care. In: Guidelines for Women's Health Care, 4th ed, ACOG, 2014. p.389.
  38. Morrow JI, Hunt SJ, Russell AJ, et al. Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2009; 80:506.
  39. Ban L, Fleming KM, Doyle P, et al. Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study. PLoS One 2015; 10:e0131130.
  40. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000; 343:1608.
  41. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 2005; 105:675.
  42. American Diabetes Association. 13. Management of Diabetes in Pregnancy. Diabetes Care 2017; 40:S114.
  43. Correa A, Gilboa SM, Botto LD, et al. Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. Am J Obstet Gynecol 2012; 206:218.e1.
  44. Parker SE, Yazdy MM, Tinker SC, et al. The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida. Am J Obstet Gynecol 2013; 209:239.e1.
  45. Wentzel P, Gäreskog M, Eriksson UJ. Folic acid supplementation diminishes diabetes- and glucose-induced dysmorphogenesis in rat embryos in vivo and in vitro. Diabetes 2005; 54:546.
  46. Anderson CA, Beresford SA, McLerran D, et al. Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial. Mol Nutr Food Res 2013; 57:637.
  47. Guinotte CL, Burns MG, Axume JA, et al. Methylenetetrahydrofolate reductase 677C-->T variant modulates folate status response to controlled folate intakes in young women. J Nutr 2003; 133:1272.
  48. Liu S, Joseph KS, Luo W, et al. Effect of Folic Acid Food Fortification in Canada on Congenital Heart Disease Subtypes. Circulation 2016; 134:647.
  49. 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.
  50. Xu A, Cao X, Lu Y, et al. A Meta-Analysis of the Relationship Between Maternal Folic Acid Supplementation and the Risk of Congenital Heart Defects. Int Heart J 2016; 57:725.
  51. Badovinac RL, Werler MM, Williams PL, et al. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol 2007; 79:8.
  52. Bienengräber V, Malek FA, Möritz KU, et al. Is it possible to prevent cleft palate by prenatal administration of folic acid? An experimental study. Cleft Palate Craniofac J 2001; 38:393.
  53. Zhang Q, Wang Y, Xin X, et al. Effect of folic acid supplementation on preterm delivery and small for gestational age births: A systematic review and meta-analysis. Reprod Toxicol 2017; 67:35.
  54. Hodgetts VA, Morris RK, Francis A, et al. Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis. BJOG 2015; 122:478.
  55. Gao Y, Sheng C, Xie RH, et al. New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review. PLoS One 2016; 11:e0165626.
  56. Shim SM, Yun YU, Kim YS. Folic acid alone or multivitamin containing folic acid intake during pregnancy and the risk of gestational hypertension and preeclampsia through meta-analyses. Obstet Gynecol Sci 2016; 59:110.
  57. Castro K, Klein Lda S, Baronio D, et al. Folic acid and autism: What do we know? Nutr Neurosci 2016; 19:310.
  58. Mantovani E, Filippini F, Bortolus R, Franchi M. Folic acid supplementation and preterm birth: results from observational studies. Biomed Res Int 2014; 2014:481914.
  59. Balogun OO, da Silva Lopes K, Ota E, et al. Vitamin supplementation for preventing miscarriage. Cochrane Database Syst Rev 2016; :CD004073.
  60. Lumley J, Watson L, Watson M, Bower C. Modelling the potential impact of population-wide periconceptional folate/multivitamin supplementation on multiple births. BJOG 2001; 108:937.
  61. Ericson A, Källén B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001; 4:63.
  62. Li Z, Gindler J, Wang H, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003; 361:380.
  63. Geraghty AA, Lindsay KL, Alberdi G, et al. Nutrition During Pregnancy Impacts Offspring's Epigenetic Status-Evidence from Human and Animal Studies. Nutr Metab Insights 2015; 8:41.
  64. Veeranki SP, Gebretsadik T, Dorris SL, et al. Association of folic acid supplementation during pregnancy and infant bronchiolitis. Am J Epidemiol 2014; 179:938.
  65. Blatter J, Han YY, Forno E, et al. Folate and asthma. Am J Respir Crit Care Med 2013; 188:12.
  66. Granell R, Heron J, Lewis S, et al. The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort. Clin Exp Allergy 2008; 38:320.
  67. Bekkers MB, Elstgeest LE, Scholtens S, et al. Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy. Eur Respir J 2012; 39:1468.
  68. Magdelijns FJ, Mommers M, Penders J, et al. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics 2011; 128:e135.
  69. Crider KS, Cordero AM, Qi YP, et al. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr 2013; 98:1272.
  70. Charles D, Ness AR, Campbell D, et al. Taking folate in pregnancy and risk of maternal breast cancer. BMJ 2004; 329:1375.
  71. Oakley GP, Mandel JS. Folic acid fortification remains an urgent health priority. BMJ 2004; 329:1376.
  72. Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, et al. Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr 2017; 106:878.
  73. Chatzi L, Papadopoulou E, Koutra K, et al. Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: the mother-child cohort 'Rhea' study in Crete, Greece. Public Health Nutr 2012; 15:1728.
  74. Mills JL. Preventing folate-related neural tube defects: Problem solved, or not? Birth Defects Res A Clin Mol Teratol 2015; 103:469.
  75. De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007; 357:135.
  76. Epidemiology and control of neural tube defects. In: Monograph in Epidemiology and Biostatistics, Little J, Elwood JM (Eds), Oxford University Press, Oxford 1992. Vol 20.
  77. Noventa M, Vitagliano A, Quaranta M, et al. Preventive and Therapeutic Role of Dietary Inositol Supplementation in Periconceptional Period and During Pregnancy: A Summary of Evidences and Future Applications. Reprod Sci 2016; 23:278.