Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation


The clinical significance of periconceptional folic acid supplementation (FAS) in the prevention of neonatal neural tube defects (NTDs) has been recognized for decades. Epidemiological data and experimental findings have consistently been indicating an association between folate deficiency in the first trimester of pregnancy and poor fetal development as well as offspring health (i.e., NTDs, isolated orofacial clefts, neurodevelopmental disorders). Moreover, compelling evidence has suggested adverse effects of folate overload during perinatal period on offspring health (i.e., immune diseases, autism, lipid disorders). In addition to several single-nucleotide polymorphisms (SNPs) in genes related to folate one-carbon metabolism (FOCM), folate concentrations in maternal serum/plasma/red blood cells must be considered when counseling FAS. Epigenetic information encoded by 5-methylcytosines (5mC) plays a critical role in fetal development and offspring health. S-adenosylmethionine (SAM), a methyl donor for 5mC, could be derived from FOCM. As such, folic acid plays a double-edged sword role in offspring health via mediating DNA methylation. However, the underlying epigenetic mechanism is still largely unclear. In this review, we summarized the link across DNA methylation, maternal FAS, and offspring health to provide more evidence for clinical guidance in terms of precise FAS dosage and time point. Future studies are, therefore, required to set up the reference intervals of folate concentrations at different trimesters of pregnancy for different populations and to clarify the epigenetic mechanism for specific offspring diseases.

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  1. 1.

    Wolff T, Witkop CT, Miller T, Syed SB, U.S. Preventive Services Task Force. Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the U.S. preventive services task force. Ann Intern Med. 2009;150(9):632–9.

    PubMed  Google Scholar 

  2. 2.

    Periconceptional folic acid supplementation to prevent neural tube defects []. Accessed 11 May 2019.

  3. 3.

    Racial/ethnic differences in the birth prevalence of spina bifida - United States, 1995–2005. MMWR Morb Mortal Wkly Rep. 2009;57(53):1409–13.

  4. 4.

    Centers for Disease C. Prevention: Racial/ethnic differences in the birth prevalence of spina bifida - United States, 1995–2005. MMWR Morb Mortal Wkly Rep. 2009;57(53):1409–13.

    Google Scholar 

  5. 5.

    Grosse SD, Berry RJ, Mick Tilford J, 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.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Ami N, Bernstein M, Boucher F, Rieder M, Parker L, Canadian Paediatric Society, Drug Therapy and Hazardous Substances Committee. Folate and neural tube defects: the role of supplements and food fortification. Paediatr Child Health. 2016;21(3):145–54.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Williams J, Mai CT, Mulinare J, et al. Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;64(1):1–5.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Caffrey A, Irwin RE, McNulty H, et al. Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: epigenetic analysis from a randomized controlled trial. Am J Clin Nutr. 2018;107(4):566–75.

    PubMed  Google Scholar 

  9. 9.

    Richmond RC, Sharp GC, Herbert G, et al. The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen folic acid supplementation trial (AFAST). Int J Epidemiol. 2018.

  10. 10.

    Steegers-Theunissen RP, Twigt J, Pestinger V, Sinclair KD. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Reprod Update. 2013;19(6):640–55.

    CAS  PubMed  Google Scholar 

  11. 11.

    Lambrot R, Xu C, Saint-Phar S, et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun. 2013;4:2889.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Sahara Y, Matsuzawa D. Paternal methyl donor deficient diets during development affect male offspring behavior and memory-related gene expression in mice. Dev Psychobiol. 2019;61(1):17–28.

    CAS  PubMed  Google Scholar 

  13. 13.

    Ly L, Chan D, Aarabi M, Landry M, Behan NA, MacFarlane A, et al. Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation. Mol Hum Reprod. 2017;23(7):461–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ryan DP, Henzel KS, Pearson BL, et al. A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice. Mol Psychiatry. 2018;23(5):1345–55.

    CAS  PubMed  Google Scholar 

  15. 15.

    De Sanctis V, Candini G, Giovannini M, et al. Abnormal seminal parameters in patients with thalassemia intermedia and low serum folate levels. Pediatr Endocrinol Rev. 2011;8(Suppl 2):310–3.

    PubMed  Google Scholar 

  16. 16.

    Song CX, Szulwach KE, Dai Q, Fu Y, Mao SQ, Lin L, et al. Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell. 2013;153(3):678–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517–34.

    CAS  PubMed  Google Scholar 

  18. 18.

    Bar S, Benvenisty N. Epigenetic aberrations in human pluripotent stem cells. EMBO J. 2019;38(12).

  19. 19.

    Yu M, Hon GC, Szulwach KE, et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell. 2012;149(6):1368–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Globisch D, Munzel M, Muller M, et al. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One. 2010;5(12):e15367.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Ko M, An J, Rao A. DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr Opin Cell Biol. 2015;37:91–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Shen L, Wu H, Diep D, et al. Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell. 2013;153(3):692–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Chang H, Zhang T, Zhang Z, Bao R, Fu C, Wang Z, et al. Tissue-specific distribution of aberrant DNA methylation associated with maternal low-folate status in human neural tube defects. J Nutr Biochem. 2011;22(12):1172–7.

    CAS  PubMed  Google Scholar 

  24. 24.

    Ford TC, Downey LA, Simpson T. The effect of a high-dose vitamin B multivitamin supplement on the relationship between brain metabolism and blood biomarkers of oxidative stress: a randomized control trial. Nutrients. 2018;10(12).

  25. 25.

    Cui S, Lv X, Li W, Li Z, Liu H, Gao Y, et al. Folic acid modulates VPO1 DNA methylation levels and alleviates oxidative stress-induced apoptosis in vivo and in vitro. Redox Biol. 2018;19:81–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    An Y, Feng L, Zhang X, et al. Dietary intakes and biomarker patterns of folate, vitamin B6, and vitamin B12 can be associated with cognitive impairment by hypermethylation of redox-related genes NUDT15 and TXNRD1. Clin Epigenitics. 2019;11(1):139.

    Google Scholar 

  27. 27.

    Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS. Spina bifida. Lancet. 2004;364(9448):1885–95.

    PubMed  Google Scholar 

  28. 28.

    Bjorkegren K, Svardsudd K. Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly swedes: a population-based study. J Intern Med. 2003;254(4):343–52.

    CAS  PubMed  Google Scholar 

  29. 29.

    Halsted CH. The intestinal absorption of dietary folates in health and disease. J Am Coll Nutr. 1989;8(6):650–8.

    CAS  PubMed  Google Scholar 

  30. 30.

    Russell RM, Golner BB, Krasinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med. 1988;112(4):458–63.

    CAS  PubMed  Google Scholar 

  31. 31.

    Forssen KM, Jagerstad MI, Wigertz K, et al. Folates and dairy products: a critical update. J Am Coll Nutr. 2000;19(2 Suppl):100s–10s.

    CAS  PubMed  Google Scholar 

  32. 32.

    Buttner BE, Ohrvik VE, Witthoft CM, et al. Quantification of isotope-labelled and unlabelled folates in plasma, ileostomy and food samples. Anal Bioanal Chem. 2011;399(1):429–39.

    PubMed  Google Scholar 

  33. 33.

    Ohrvik VE, Buttner BE, Rychlik M, et al. Folate bioavailability from breads and a meal assessed with a human stable-isotope area under the curve and ileostomy model. Am J Clin Nutr. 2010;92(3):532–8.

    PubMed  Google Scholar 

  34. 34.

    Ohrvik VE, Witthoft CM. Human folate bioavailability. Nutrients. 2011;3(4):475–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Wills L. Treatment of “pernicious anaemia of pregnancy” and “tropical anaemia”. Br Med J. 1931;1(3676):1059–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hibbard BM, Hibbard ED, Jeffcoate TN. Folic acid and reproduction. Acta Obstet Gynecol Scand. 1965;44(3):375–400.

    CAS  PubMed  Google Scholar 

  37. 37.

    Hibbard BM, Hibbard ED. Folate deficiency in pregnancy. Br Med J. 1968;4(5628):452–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Giles C. An account of 335 cases of megaloblastic anaemia of pregnancy and the puerperium. J Clin Pathol. 1966;19(1):1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hansen HA. The incidence of pernicious anaemia and the etiology of folic acid deficiency in pregnancy. Acta Obstet Gynecol Scand. 1967;46(S7):113–5.

    CAS  PubMed  Google Scholar 

  40. 40.

    Willoughby ML, Jewell FJ. Investigation of folic acid requirements in pregnancy. Br Med J. 1966;2(5529):1568–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    McStay CL, Prescott SL, Bower C, et al. Maternal folic acid supplementation during pregnancy and childhood allergic disease outcomes: a question of timing? Nutrients. 2017;9(2).

  42. 42.

    Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995;274(21):1698–702.

    CAS  PubMed  Google Scholar 

  43. 43.

    Hursthouse NA, Gray AR, Miller JC, Rose MC, Houghton LA. Folate status of reproductive age women and neural tube defect risk: the effect of long-term folic acid supplementation at doses of 140 microg and 400 microg per day. Nutrients. 2011;3(1):49–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Cordero AM, Crider KS, Rogers LM, Cannon MJ, Berry RJ. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep. 2015;64(15):421–3.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Zaganjor I, Sekkarie A, Tsang BL, et al. Describing the prevalence of neural tube defects worldwide: a systematic literature review. PLoS One. 2016;11(4):e0151586.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Johnson WG, Stenroos ES, Spychala JR, et al. New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet A. 2004;124a(4):339–45.

    PubMed  Google Scholar 

  47. 47.

    van der Linden IJ, Nguyen U, Heil SG, Franke B, Vloet S, Gellekink H, et al. Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida. Mol Genet Metab. 2007;91(1):98–103.

    PubMed  Google Scholar 

  48. 48.

    van der Linden IJ, Heil SG, Kouwenberg IC, den Heijer M, Blom HJ. The methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G>a variant is not associated with spina bifida risk in the Dutch population. Clin Genet. 2007;72(6):599–600.

    PubMed  Google Scholar 

  49. 49.

    Candito M, Rivet R, Herbeth B, et al. Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study. Am J Med Genet A. 2008;146a(9):1128–33.

    CAS  PubMed  Google Scholar 

  50. 50.

    Franke B, Vermeulen SH, Steegers-Theunissen RP, Coenen MJ, Schijvenaars MM, Scheffer H, et al. An association study of 45 folate-related genes in spina bifida: involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1). Birth Defects Res A Clin Mol Teratol. 2009;85(3):216–26.

    CAS  PubMed  Google Scholar 

  51. 51.

    Yu Y, Wang F, Bao Y, et al. Association between MTHFR gene polymorphism and NTDs in Chinese Han population. Int J Clin Exp Med. 2014;7(9):2901–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Wang Y, Liu Y, Ji W, Qin H, Wu H, Xu D, et al. Analysis of MTR and MTRR polymorphisms for neural tube defects risk association. Medicine (Baltimore). 2015;94(35):e1367.

    CAS  Google Scholar 

  53. 53.

    Meng J, Han L, Zhuang B. Association between MTHFD1 polymorphisms and neural tube defect susceptibility. J Neurol Sci. 2015;348(1–2):188–94.

    CAS  PubMed  Google Scholar 

  54. 54.

    Cheng H, Li H, Bu Z, Zhang Q, Bai B, Zhao H, et al. Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations. Mol Cell Biochem. 2015;407(1–2):51–6.

    CAS  PubMed  Google Scholar 

  55. 55.

    Wu L, Lu X, Guo J, et al. Association between ALDH1L1 gene polymorphism and neural tube defects in the Chinese Han population. Neurol Sci. 2016;37(7):1049–54.

    PubMed  Google Scholar 

  56. 56.

    Piao W, Guo J, Bao Y, Wang F, Zhang T, Huo J, et al. Analysis of polymorphisms of genes associated with folate-mediated one-carbon metabolism and neural tube defects in Chinese Han population. Birth Defects Res A Clin Mol Teratol. 2016;106(4):232–9.

    CAS  PubMed  Google Scholar 

  57. 57.

    Cao L, Wang Y, Zhang R, Dong L, Cui H, Fang Y, et al. Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway. Childs Nerv Syst. 2018;34(2):277–84.

    PubMed  Google Scholar 

  58. 58.

    KR P, Tella S, Buragadda S, et al. Interaction between maternal and paternal SHMT1 C1420T predisposes to neural tube defects in the fetus: evidence from case-control and family-based triad approaches. Birth Defects Res. 2017;109(13):1020–9.

    Google Scholar 

  59. 59.

    Dutta HK, Borbora D, Baruah M, Narain K. Evidence of gene-gene interactions between MTHFD1 and MTHFR in relation to anterior encephalocele susceptibility in Northeast India. Birth Defects Res. 2017;109(6):432–44.

    CAS  PubMed  Google Scholar 

  60. 60.

    Paul S, Sadhukhan S, Munian D, et al. Association of FOLH1, DHFR, and MTHFR gene polymorphisms with susceptibility of Neural Tube Defects: A case control study from Eastern India. Birth Defects Res. 2018;110(14):1129–38.

    CAS  PubMed  Google Scholar 

  61. 61.

    Fang Y, Zhang R, Zhi X, Zhao L, Cao L, Wang Y, et al. Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of northern China. Childs Nerv Syst. 2018;34(4):725–9.

    PubMed  Google Scholar 

  62. 62.

    Cai CQ, Fang YL, Shu JB, et al. Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway. Ital J Pediatr. 2019;45(1):37.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Morales de Machin A, Mendez K, Solis E, et al. C677T polymorphism of the methylentetrahydrofolate reductase gene in mothers of children affected with neural tube defects. Investig Clin. 2015;56(3):284–95.

    Google Scholar 

  64. 64.

    Shaw GM, Lu W, Zhu H, et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet. 2009;10:49.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Crider KS, Devine O, Hao L, et al. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014;349:g4554.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Liu ZZ, Zhang JT, Liu D, Hao YH, Chang BM, Xie J, et al. Interaction between maternal 5,10-methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene variants to increase the risk of fetal neural tube defects in a Shanxi Han population. Chin Med J. 2013;126(5):865–9.

    CAS  PubMed  Google Scholar 

  67. 67.

    Crider KS, Zhu JH, Hao L, et al. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr. 2011;93(6):1365–72.

    CAS  PubMed  Google Scholar 

  68. 68.

    Tsang BL, Devine OJ, Cordero AM, Marchetta CM, Mulinare J, Mersereau P, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286–94.

    CAS  PubMed  Google Scholar 

  69. 69.

    Martinez CA, Northrup H, Lin JI, et al. Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. Am J Obstet Gynecol. 2009;201(4):394.e391–11.

    Google Scholar 

  70. 70.

    Pangilinan F, Molloy AM, Mills JL, et al. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects. BMC Med Genet. 2012;13:62.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Etheredge AJ, Finnell RH, Carmichael SL, et al. Maternal and infant gene-folate interactions and the risk of neural tube defects. Am J Med Genet A. 2012;158a(10):2439–46.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Smith DE, Hornstra JM, Kok RM, Blom HJ, Smulders YM. Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism. Clin Chem Lab Med. 2013;51(8):1643–50.

    CAS  PubMed  Google Scholar 

  73. 73.

    Rochtus A, Jansen K, Van Geet C, et al. Nutri-epigenomic studies related to neural tube defects: does Folate affect neural tube closure via changes in DNA methylation? Mini Rev Med Chem. 2015;15(13):1095–102.

    CAS  PubMed  Google Scholar 

  74. 74.

    Chang S, Wang L, Guan Y, Shangguan S, du Q, Wang Y, et al. Long interspersed nucleotide element-1 hypomethylation in folate-deficient mouse embryonic stem cells. J Cell Biochem. 2013;114(7):1549–58.

    CAS  PubMed  Google Scholar 

  75. 75.

    Wang L, Wang F, Guan J, et al. Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. Am J Clin Nutr. 2010;91(5):1359–67.

    CAS  PubMed  Google Scholar 

  76. 76.

    Wang L, Chang S, Guan J, Shangguan S, Lu X, Wang Z, et al. Tissue-specific methylation of long interspersed nucleotide Element-1 of homo sapiens (L1Hs) during human embryogenesis and roles in neural tube defects. Curr Mol Med. 2015;15(5):497–507.

    CAS  PubMed  Google Scholar 

  77. 77.

    Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol. 2002;192(3):245–58.

    CAS  PubMed  Google Scholar 

  78. 78.

    Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. Rna. 2007;13(3):313–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Liu Z, Wang Z, Li Y, Ouyang S, Chang H, Zhang T, et al. Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects. Eur J Hum Genet. 2012;20(5):516–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Wu L, Wang L, Shangguan S, et al. Altered methylation of IGF2 DMR0 is associated with neural tube defects. Mol Cell Biochem. 2013;380(1–2):33–42.

    CAS  PubMed  Google Scholar 

  81. 81.

    Hartmann W, Koch A, Brune H, Waha A, Schüller U, Dani I, et al. Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. Am J Pathol. 2005;166(4):1153–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, et al. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006;103(28):10684–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Bai B, Zhang Q, Liu X, Miao C, Shangguan S, Bao Y, et al. Different epigenetic alterations are associated with abnormal IGF2/Igf2 upregulation in neural tube defects. PLoS One. 2014;9(11):e113308.

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Williamson CM, Turner MD, Ball ST, Nottingham WT, Glenister P, Fray M, et al. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet. 2006;38(3):350–5.

    CAS  PubMed  Google Scholar 

  85. 85.

    Wang L, Chang S, Wang Z, et al. Altered GNAS imprinting due to folic acid deficiency contributes to poor embryo development and may lead to neural tube defects. Oncotarget. 2017;8(67):110797–810.

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Haggarty P, Hoad G, Campbell DM, Horgan GW, Piyathilake C, McNeill G. Folate in pregnancy and imprinted gene and repeat element methylation in the offspring. Am J Clin Nutr. 2013;97(1):94–9.

    CAS  PubMed  Google Scholar 

  87. 87.

    Gonseth S, Shaw GM, Roy R, et al. Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk. Epigenetics. 2019;14(2):198–213.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yang X, Huang Y, Sun C, et al. Maternal prenatal folic acid supplementation programs offspring lipid metabolism by aberrant DNA methylation in hepatic ATGL and adipose LPL in rats. Nutrients. 2017;9(9).

  89. 89.

    Li W, Li Z, Li S, et al. Periconceptional folic acid supplementation benefit to development of early sensory-motor function through increase DNA methylation in rat offspring. Nutrients. 2018;10(3).

  90. 90.

    Mofolorunso A, Skjaerven KH, Jakt LM, et al. Parental micronutrient deficiency distorts liver DNA methylation and expression of lipid genes associated with a fatty-liver-like phenotype in offspring. J Diet Suppl. 2018;8(1):3055.

    Google Scholar 

  91. 91.

    Yang Y, Yang S, Liu J, Feng Y, Qi F, Zhao R. DNA Hypomethylation of GR promoters is associated with GR activation and BDNF/AKT/ERK1/2-induced hippocampal neurogenesis in mice derived from folic-acid-supplemented dams. Mol Nutr Food Res. 2019;63(12):e1801334.

    PubMed  Google Scholar 

  92. 92.

    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.

    CAS  PubMed  Google Scholar 

  93. 93.

    Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey D, Abyholm F, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. Bmj. 2007;334(7591):464.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Sharp GC, Ho K, Davies A, et al. Distinct DNA methylation profiles in subtypes of orofacial cleft. Clin Epigenetics. 2017;9:63.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Pierre G. Neurodegenerative disorders and metabolic disease. Arch Dis Child. 2013;98(8):618–24.

    PubMed  Google Scholar 

  96. 96.

    Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry. 2017;4(4):339–46.

    PubMed  Google Scholar 

  97. 97.

    Jasarevic E, Howerton CL, Howard CD, et al. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology. 2015;156(9):3265–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kofink D, Boks MP, Timmers HT, et al. Epigenetic dynamics in psychiatric disorders: environmental programming of neurodevelopmental processes. Neurosci Biobehav Rev. 2013;37(5):831–45.

    PubMed  Google Scholar 

  99. 99.

    O'Donnell KA, Gaudreau H, Colalillo S, Steiner M, Atkinson L, Moss E, et al. The maternal adversity, vulnerability and neurodevelopment project: theory and methodology. Can J Psychiatr. 2014;59(9):497–508.

    Google Scholar 

  100. 100.

    Kruman II, Mouton PR, Emokpae R Jr, et al. Folate deficiency inhibits proliferation of adult hippocampal progenitors. Neuroreport. 2005;16(10):1055–9.

    CAS  PubMed  Google Scholar 

  101. 101.

    Blaise SA, Nedelec E, Schroeder H, et al. Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats. Am J Pathol. 2007;170(2):667–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Craciunescu CN, Brown EC, Mar MH, Albright CD, Nadeau MR, Zeisel SH. Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr. 2004;134(1):162–6.

    CAS  PubMed  Google Scholar 

  103. 103.

    Wang X, Li W, Li Z, et al. Maternal folic acid supplementation during pregnancy promotes neurogenesis and synaptogenesis in neonatal rat offspring. Cereb Cortex. 2018.

  104. 104.

    Deniz BF, Confortim HD, Deckmann I, Miguel PM, Bronauth L, de Oliveira BC, et al. Folic acid supplementation during pregnancy prevents cognitive impairments and BDNF imbalance in the hippocampus of the offspring after neonatal hypoxia-ischemia. J Nutr Biochem. 2018;60:35–46.

    CAS  PubMed  Google Scholar 

  105. 105.

    Neumann D, Herbert SE, Peterson ER, Underwood L, Morton SMB, Waldie KE. A longitudinal study of antenatal and perinatal risk factors in early childhood cognition: evidence from growing up in New Zealand. Early Hum Dev. 2019;132:45–51.

    PubMed  Google Scholar 

  106. 106.

    Bekkers MB, Elstgeest LE, Scholtens S, Haveman-Nies A, de Jongste JC, Kerkhof M, et al. Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy. Eur Respir J. 2012;39(6):1468–74.

    CAS  PubMed  Google Scholar 

  107. 107.

    Dunstan JA, West C, McCarthy S, et al. The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood. Allergy. 2012;67(1):50–7.

    CAS  PubMed  Google Scholar 

  108. 108.

    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(2):320–8.

    CAS  PubMed  Google Scholar 

  109. 109.

    Haberg SE, London SJ, Nafstad P, et al. Maternal folate levels in pregnancy and asthma in children at age 3 years. J Allergy Clin Immunol. 2011;127(1):262–4 264 e261.

    CAS  PubMed  Google Scholar 

  110. 110.

    Haberg SE, London SJ, Stigum H, et al. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child. 2009;94(3):180–4.

    CAS  PubMed  Google Scholar 

  111. 111.

    Kiefte-de Jong JC, Timmermans S, Jaddoe VW, Hofman A, Tiemeier H, Steegers EA, et al. High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring. J Nutr. 2012;142(4):731–8.

    CAS  PubMed  Google Scholar 

  112. 112.

    Kim JH, Jeong KS, Ha EH, Park H, Ha M, Hong YC, et al. Relationship between prenatal and postnatal exposures to folate and risks of allergic and respiratory diseases in early childhood. Pediatr Pulmonol. 2015;50(2):155–63.

    CAS  PubMed  Google Scholar 

  113. 113.

    Magdelijns FJ, Mommers M, Penders J, Smits L, Thijs C. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics. 2011;128(1):e135–44.

    PubMed  Google Scholar 

  114. 114.

    Tuokkola J, Luukkainen P, Kaila M, Takkinen HM, Niinistö S, Veijola R, et al. Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring. Br J Nutr. 2016;116(4):710–8.

    CAS  PubMed  Google Scholar 

  115. 115.

    Whitrow MJ, Moore VM, Rumbold AR, et al. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;170(12):1486–93.

    PubMed  Google Scholar 

  116. 116.

    Fortes C, Mastroeni S, Mannooranparampil TJ, di Lallo D. Pre-natal folic acid and iron supplementation and atopic dermatitis in the first 6 years of life. Arch Dermatol Res. 2019;311(5):361–7.

    CAS  PubMed  Google Scholar 

  117. 117.

    Iscan B, Tuzun F, Eroglu Filibeli B, et al. Effects of maternal folic acid supplementation on airway remodeling and allergic airway disease development. J Matern Fetal Neonatal Med. 2019;32(18):2970–8.

    CAS  PubMed  Google Scholar 

  118. 118.

    Martino D, Dang T, Sexton-Oates A, et al. Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J Allergy Clin Immunol. 2015;135(5):1319–28 e1311–1312.

    CAS  PubMed  Google Scholar 

  119. 119.

    Martino D, Joo JE, Sexton-Oates A, et al. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. Epigenetics. 2014;9(7):998–1006.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Berni Canani R, Paparo L, Nocerino R, et al. Differences in DNA methylation profile of Th1 and Th2 cytokine genes are associated with tolerance acquisition in children with IgE-mediated cow's milk allergy. Clin Epigenetics. 2015;7:38.

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Raghavan R, Zuckerman B, Hong X, et al. Fetal and infancy growth pattern, cord and early childhood plasma leptin, and development of autism spectrum disorder in the Boston birth cohort. Autism Res. 2018;11(10):1416–31.

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, et al. Maternal multivitamin intake, plasma folate and vitamin B12 levels and autism spectrum disorder risk in offspring. Paediatr Perinat Epidemiol. 2018;32(1):100–11.

    PubMed  Google Scholar 

  123. 123.

    Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH. Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia. 2014;57(1):110–21.

    CAS  PubMed  Google Scholar 

  124. 124.

    Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune maternal nutrition study. Diabetologia. 2008;51(1):29–38.

    CAS  PubMed  Google Scholar 

  125. 125.

    Schaible TD, Harris RA, Dowd SE, et al. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet. 2011;20(9):1687–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Cho CE, Sanchez-Hernandez D, Reza-Lopez SA, et al. High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics. 2013;8(7):710–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank Jun-Ting Zhou for preparing Fig. 3B (Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China). We also would like to appreciate Professor Wei Zhang (Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, USA) for manuscript review.


This research was supported by grants from the National Natural Science Foundation of China (81771543, 81972009), and Health Commission of Hubei Province Scientific Research Project (WJ2019C002, WJ2019H005).

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Correspondence to Song-Mei Liu or Yuan-Zhen Zhang.

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Liu, HY., Liu, SM. & Zhang, YZ. Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation. Reprod. Sci. 27, 963–976 (2020).

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  • Folic acid supplementation
  • DNA methylation
  • Offspring health