Folic acid supplementation in pregnancy: established benefits, emerging evidence and public health implications

Authors

  • Suhas Srinivasan Department of Nutrition and Dietetics, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
  • Rakshitha C. N. Department of Food Science and Nutrition, Bharathi College, Mandya, Karnataka, India
  • Vanitha Reddy P. Department of Nutrition and Dietetics, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India

DOI:

https://doi.org/10.18203/2394-6040.ijcmph20261815

Keywords:

Epigenetics, Folic acid, Foetal development, Neural tube defects, Maternal nutrition

Abstract

Folic acid supplementation during pregnancy is one of the most effective nutritional interventions for preventing neural tube defects (NTDs). This narrative review synthesizes evidence from randomized controlled trials, observational studies, systematic reviews, and mechanistic research to evaluate the role of folic acid in maternal and foetal health. Robust and consistent evidence demonstrates that periconceptional folic acid supplementation substantially reduces the risk of NTDs, providing the scientific basis for global supplementation guidelines and mandatory food fortification programmes. Beyond NTD prevention, maternal folate status has been associated with a range of pregnancy and offspring outcomes, including foetal growth, neurodevelopment, and long-term metabolic health. These associations are supported by emerging evidence from epidemiological and experimental studies, with epigenetic mechanisms proposed as a key biological pathway. However, evidence for these broader effects remains less consistent and is largely observational in nature. In the post-fortification era, concerns have emerged regarding excessive folic acid intake, including the potential accumulation of unmetabolised folic acid and disruption of balanced one-carbon metabolism. This review critically evaluates established benefits, emerging evidence, and ongoing controversies surrounding folic acid supplementation in pregnancy, and identifies priorities for future research and public health practice.

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References

Bailey LB. Folate in health and disease. 2nd edition. Boca Raton (FL): CRC Press. 2009.

Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med. 2004;350:101-3. DOI: https://doi.org/10.1056/NEJMp038186

MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338(8760):131-7. DOI: https://doi.org/10.1016/0140-6736(91)90133-A

Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327(26):1832-5. DOI: https://doi.org/10.1056/NEJM199212243272602

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. N Engl J Med. 1999;341(20):1485-90. DOI: https://doi.org/10.1056/NEJM199911113412001

Olney RS, Mulinare J. Trends in neural tube defect prevalence, folic acid fortification, and vitamin supplement use. Semin Perinatol. 2002;26(4):277-85. DOI: https://doi.org/10.1053/sper.2002.34773

Blencowe H, Kancherla V, Moorthie S, Darlison MW, Modell B. Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis. Ann N Y Acad Sci. 2018;1414(1):31-46. DOI: https://doi.org/10.1111/nyas.13548

Cai S, Quan S, Yang G, Ye Q, Chen M, Yu H, et al. One-carbon metabolism and mammalian pregnancy outcomes. Mol Nutr Food Res. 2021;65(2):2000734. DOI: https://doi.org/10.1002/mnfr.202000734

Tamura T, Picciano MF. Folate and human reproduction. Am J Clin Nutr. 2006;83(5):993-1016. DOI: https://doi.org/10.1093/ajcn/83.5.993

Caffrey A, McNulty H, Irwin RE, Walsh CP, Pentieva K. Maternal folate nutrition and offspring health: evidence and current controversies. Proc Nutr Soc. 2019;78(2):208-20. DOI: https://doi.org/10.1017/S0029665118002689

Joubert BR, den Dekker HT, Felix JF, Bohlin J, Ligthart S, Beckett E, et al. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat Commun. 2016;7:10577. DOI: https://doi.org/10.1038/ncomms10577

Plumptre L, Masih SP, Ly A, Aufreiter S, Sohn KJ, Croxford R, et al. High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. Am J Clin Nutr. 2015;102(4):848-57. DOI: https://doi.org/10.3945/ajcn.115.110783

Xu X, Zhang Y, Wang X. Risk of excess maternal folic acid supplementation in offspring. Nutrients. 2024;16(5):755. DOI: https://doi.org/10.3390/nu16050755

Wilson RD, O'Connor DL. Guideline No. 427: Folic acid and multivitamin supplementation for prevention of folic acid-sensitive congenital anomalies. J Obstet Gynaecol Can. 2022;44(6):707-19. DOI: https://doi.org/10.1016/j.jogc.2022.04.004

Molloy AM, Kirke PN, Brody LC, Scott JM, Mills JL. Effects of folate and vitamin B12 deficiencies during pregnancy on Foetal, infant, and child development. Food Nutr Bull. 2008;29:S101-11. DOI: https://doi.org/10.1177/15648265080292S114

van der Put NM, Eskes TK, Blom HJ. Is the common 677C→T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? QJM. 1997;90(2):111-5. DOI: https://doi.org/10.1093/qjmed/90.2.111

Liu S, Joseph KS, Luo W, León JA, Lisonkova S, Van den Hof M, et al. Effect of folic acid food fortification in Canada on congenital heart disease subtypes. Circulation. 2016;134(9):647-55. DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.022126

Feng Y, Wang S, Chen R, Tong X, Wu Z, Mo X, et al. Maternal folic acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies. Sci Rep. 2015;5:8506. DOI: https://doi.org/10.1038/srep08506

Mao B, Qiu J, Zhao N, Shao Y, Dai W, He X, et al. Maternal folic acid supplementation and dietary folate intake and congenital heart defects. PLoS One. 2017;12(11):e0187996. DOI: https://doi.org/10.1371/journal.pone.0187996

Hobbs CA, Cleves MA, Karim MA, Zhao W, MacLeod SL. Maternal folate-related gene environment interactions and congenital heart defects. Obstet Gynecol. 2010;116(2 Pt 1):316-22. DOI: https://doi.org/10.1097/AOG.0b013e3181e80979

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. DOI: https://doi.org/10.1136/bmj.39079.618287.0B

Wehby GL, Murray JC. Folic acid and orofacial clefts: a review of the evidence. Oral Dis. 2010;16(1):11-9. DOI: https://doi.org/10.1111/j.1601-0825.2009.01587.x

De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, Rayco-Solon P, et al. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2015;2015(12):CD007950. DOI: https://doi.org/10.1002/14651858.CD007950.pub3

Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet C Semin Med Genet. 2004;125C(1):12-21. DOI: https://doi.org/10.1002/ajmg.c.30004

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(8):680-9. DOI: https://doi.org/10.1016/S1701-2163(16)32227-7

Crider KS, Bailey LB, Berry RJ. Folic acid food fortification—its history, effect, concerns, and future directions. Nutrients. 2011;3(3):370-84. DOI: https://doi.org/10.3390/nu3030370

Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;(7):CD004736. DOI: https://doi.org/10.1002/14651858.CD004736.pub5

World Health Organization. Periconceptional folic acid supplementation to prevent neural tube defects: WHO recommendations on antenatal care for a positive pregnancy experience. 2016. Available at: https://www.who.int/publications/i/item/9789241549912. Accessed on 25 February 2026.

Cui H, Zhang N, An J, Zeng X, Zhao Y, Sun X, et al. Maternal folic acid supplementation to prevent preeclampsia: a systematic review and meta-analysis. Complement Ther Med. 2024;82:103052. DOI: https://doi.org/10.1016/j.ctim.2024.103052

Liu C, Liu C, Wang Q, Zhang Z. Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis. Arch Gynecol Obstet. 2018;298(4):697-704. DOI: https://doi.org/10.1007/s00404-018-4823-4

Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-22. DOI: https://doi.org/10.1056/NEJMoa1704559

Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GD, et al. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Med. 2009;6(5):e1000061. DOI: https://doi.org/10.1371/journal.pmed.1000061

Catov JM, Bodnar LM, Olsen J, Olsen S, Nohr EA. Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort. Am J Clin Nutr. 2011;94(3):906-12. DOI: https://doi.org/10.3945/ajcn.111.012393

Kanasaki K, Kumagai A. The impact of micronutrient deficiency on pregnancy complications and developmental origins of health and disease. J Obstet Gynaecol Res. 2021;47(6):1965-72. DOI: https://doi.org/10.1111/jog.14770

Timmermans S, Jaddoe VW, Hofman A, Steegers-Theunissen RP, Steegers EA. Periconception folic acid supplementation, Foetal growth and the risks of low birth weight and preterm birth: the Generation R Study. Br J Nutr. 2009;102(5):777-85. DOI: https://doi.org/10.1017/S0007114509288994

Yajnik CS, Deshmukh US. Foetal programming: maternal nutrition and role of one-carbon metabolism. Rev Endocr Metab Disord. 2012;13(2):121-7. DOI: https://doi.org/10.1007/s11154-012-9214-8

Guo H, Mao B, Wang M, Liu Q, Yang L, Xie Y, et al. Folic acid supplementation, dietary folate intake and risk of small for gestational age in China. Public Health Nutr. 2020;23(11):1965-73. DOI: https://doi.org/10.1017/S1368980019003331

Fekete K, Berti C, Trovato M, Lohner S, Dullemeijer C, Souverein OW, et al. Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutr J. 2012;11:75. DOI: https://doi.org/10.1186/1475-2891-11-75

Roth C, Magnus P, Schjølberg S, Stoltenberg C, Surén P, McKeague IW, et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA. 2011;306(14):1566-73. DOI: https://doi.org/10.1001/jama.2011.1433

Villamor E, Rifas-Shiman SL, Gillman MW, Oken E. Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr Perinat Epidemiol. 2012;26(4):328-35. DOI: https://doi.org/10.1111/j.1365-3016.2012.01264.x

Julvez J, Fortuny J, Mendez M, Torrent M, Ribas-Fitó N, Sunyer J. Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. Paediatr Perinat Epidemiol. 2009;23(3):199-206. DOI: https://doi.org/10.1111/j.1365-3016.2009.01032.x

Veena SR, Krishnaveni GV, Srinivasan K, Wills AK, Muthayya S, Kurpad AV, et al. Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10-year-old children in South India. J Nutr. 2010;140(5):1014-22. DOI: https://doi.org/10.3945/jn.109.118075

Chatzi L, Papadopoulou E, Koutra K, Roumeliotaki T, Georgiou V, Stratakis N, 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(9):1728-36. DOI: https://doi.org/10.1017/S1368980012000067

Valera-Gran D, García de la Hera M, Navarrete-Muñoz EM, Fernandez-Somoano A, Tardón A, Julvez J, et al. Folic acid supplements during pregnancy and child psychomotor development after the first year of life. JAMA Pediatr. 2014;168(11):e142611. DOI: https://doi.org/10.1001/jamapediatrics.2014.2611

Abate BB, Tusa BS, Sendekie AK, Temesgen D, Mekuria K, Alamaw AW, et al. The association between maternal prenatal folic acid and multivitamin supplementation and autism spectrum disorders in offspring: An umbrella review. PLoS One. 2025;20(11):e0334852. DOI: https://doi.org/10.1371/journal.pone.0334852

Zou R, El Marroun H, Cecil C, Jaddoe VWV, Hillegers M, Tiemeier H, et al. Maternal folate levels during pregnancy and offspring brain development in late childhood. Clin Nutr. 2021;40(5):3391-400. DOI: https://doi.org/10.1016/j.clnu.2020.11.025

Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293-300. DOI: https://doi.org/10.1128/MCB.23.15.5293-5300.2003

Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341(6146):1237905. DOI: https://doi.org/10.1126/science.1237905

Spiers H, Hannon E, Schalkwyk LC, Smith R, Wong CC, O'Donovan MC, et al. Methylomic trajectories across human Foetal brain development. Genome Res. 2015;25(3):338-52. DOI: https://doi.org/10.1101/gr.180273.114

Pitkin RM. Folate and neural tube defects. Am J Clin Nutr. 2007;85(1):285S-8S. DOI: https://doi.org/10.1093/ajcn/85.1.285S

Kancherla V, Wagh K, Johnson Q, Oakley GP Jr. A 2017 global update on folic acid-preventable spina bifida and anencephaly. Birth Defects Res. 2018;110(14):1139-47. DOI: https://doi.org/10.1002/bdr2.1366

Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008;87(3):517-33. DOI: https://doi.org/10.1093/ajcn/87.3.517

Bailey RL, Mills JL, Yetley EA, Gahche JJ, Pfeiffer CM, Dwyer JT, et al. Serum unmetabolized folic acid in a nationally representative sample of adults ≥60 years in the United States, 2001–2002. Food Nutr Res. 2012;56:5610. DOI: https://doi.org/10.3402/fnr.v56i0.5616

Miller JW, Smith A, Troen AM, Mason JB, Jacques PF, Selhub J, et al. Excess folic acid and vitamin B12 deficiency: clinical implications? Food Nutr Bull. 2024;45(1 Suppl):S67-72. DOI: https://doi.org/10.1177/03795721241229503

Centers for Disease Control and Prevention. Folic acid safety, interactions, and health outcomes. CDC; 2025. Available at: https://www.cdc.gov/folic-acid/about/safety.html. Accessed on 25 February 2026.

World Health Organization. Periconceptional folate (folic acid) supplementation to prevent neural tube defects: WHO eLENA intervention guidance. 2024. Available at: https://www.who.int/tools/elena/ interventions/folate-periconceptional. Accessed on 25 February 2026.

Grosse SD, Berry RJ, Tilford JM, Kucik JE, Waitzman NJ. Retrospective assessment of cost savings from prevention: folic acid fortification and spina bifida in the U.S. Am J Prev Med. 2016;50(5 Suppl 1):S74-80. DOI: https://doi.org/10.1016/j.amepre.2015.10.012

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Published

2026-05-30

How to Cite

Srinivasan, S., C. N., R., & Reddy P., V. (2026). Folic acid supplementation in pregnancy: established benefits, emerging evidence and public health implications. International Journal Of Community Medicine And Public Health, 13(6), 3173–3182. https://doi.org/10.18203/2394-6040.ijcmph20261815

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Review Articles