Skip to main content Accessibility help

Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence

  • Elizabeth A. DeVilbiss (a1), Renee M. Gardner (a2), Craig J. Newschaffer (a1) (a3) and Brian K. Lee (a1) (a3)


Emerging evidence from epidemiological studies supports the notion that maternal folate status regulated by dietary and genetic factors early in pregnancy may influence the risk of autism spectrum disorders (ASD). In this review, we provide an overview of what is known about the role of folate in the aetiology of neurodevelopmental disorders; summarise relevant biological, genetic and epigenetic mechanisms; and synthesise the evidence from human observational studies and randomised controlled trials that have examined the relationship between maternal folate and ASD or related traits. Much of the existing literature on this topic is subject to limitations such as potential confounding by healthy behaviours and other dietary factors, and exposure assessed within limited exposure windows. As the existing evidence is inconclusive, further research remains to be conducted in order to verify this hypothesis. Complete assessment of maternal functional folate status through the pre- and peri-conceptional periods requires biological measurement of folate, vitamin B12 and homocysteine and genetic variants involved in one-carbon metabolism and epigenetic mechanisms. In addition to more complete assessment of maternal functional folate status, careful consideration of potential confounding is warranted.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence
      Available formats


Corresponding author

* Corresponding author: E. A. DeVilbiss, email


Hide All
1. Levy, SE & Mandell, D (2009) Autism. Lancet 374, 16271638.
2. Baio, J (2012) Prevalence of autism spectrum disorders: Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 61, 119.
3. Gaugler, T, Klei, L, Sanders, SJ, et al. (2014) Most genetic risk for autism resides with common variation. Nat Genet 46, 881885.
4. Sandin, S, Lichtenstein, P, Kuja-Halkola, R, et al. (2014) The familial risk of autism. JAMA 311, 17701777.
5. Schmidt, RJ, Tancredi, DJ, Ozonoff, S, et al. (2012) Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr 96, 8089.
6. Suren, P, Roth, C, Bresnahan, M, et al. (2013) Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 309, 570577.
7. Wald, N (1991) Prevention of neural tube defects – results of the Medical Research Council Vitamin Study. Lancet 338, 131137.
8. Williams J, Mai CT, Mulinare J, et al. (2015) Updated estimates of neural tube defects prevented by mandatory folic acid fortification – United States, 1995–2011. MMWR Morb Mortal Wkly Rep 64, 1–5.
9. Maestro, S, Muratori, F, Cesari, A, et al. (2005) Course of autism signs in the first year of life. Psychopathology 38, 2631.
10. Maestro, S, Muratori, F, Cavallaro, MC, et al. (2002) Attentional skills during the first 6 months of age in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 41, 12391245.
11. Schaevitz, LR & Berger-Sweeney, JE (2012) Gene-environment interactions and epigenetic pathways in autism: the importance of one-carbon metabolism. ILAR J 53, 322340.
12. Haaf, T (2006) Methylation dynamics in the early mammalian embryo: implications of genome reprogramming defects for development. Curr Top Microbiol Immunol 310, 1322.
13. Mayer, W, Niveleau, A, Walter, J, et al. (2000) Embryogenesis – demethylation of the zygotic paternal genome. Nature 403, 501502.
14. Geiman, TM & Muegge, K (2010) DNA methylation in early development. Mol Reprod Dev 77, 105113.
15. Rice, D & Barone, S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108, 511533.
16. Zeisel, SH (2011) The supply of choline is important for fetal progenitor cells. Semin Cell Dev Biol 22, 624628.
17. LaSalle, JM (2011) A genomic point-of-view on environmental factors influencing the human brain methylome. Epigenetics 6, 862869.
18. Li, E, Bestor, TH & Jaenisch, R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915926.
19. Okano, M, Bell, DW, Haber, DA, et al. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247257.
20. Niculescu, MD, Craciunescu, CN & Zeisel, SH (2006) Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 20, 4349.
21. Armstrong, D, Dunn, JK, Antalffy, B, et al. (1995) Selective dendritic alterations in the cortex of Rett syndrome. J Neuropath Exp Neur 54, 195201.
22. Kishi, N & Macklis, JD (2010) MeCP2 functions largely cell-autonomously, but also non-cell-autonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons. Exp Neurol 222, 5158.
23. Dominguez-Salas, P, Moore, SE, Baker, MS, et al. (2014) Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 5, 3746.
24. Christman, JK, Sheikhnejad, G, Dizik, M, et al. (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14, 551557.
25. Chango, A, Boisson, F, Barbe, F, et al. (2000) The effect of 677C->T and 1298A->C mutations on plasma homocysteine and 5, 10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 83, 593596.
26. Pu, D, Shen, Y & Wu, J (2013) Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res 6, 384392.
27. Steinfeld, R, Grapp, M, Kraetzner, R, et al. (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85, 354363.
28. Miller, AL (2008) The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 13, 216226.
29. Chugani, DC, Muzik, O, Behen, M, et al. (1999) Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 45, 287295.
30. El-Ansary, AK, Ben Bacha, AG & Al-Ayahdi, LY (2011) Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis 10, 63.
31. Mattson, MP & Shea, TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26, 137146.
32. Craciunescu, CN, Brown, EC, Mar, M-H, et al. (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr 134, 162166.
33. Greenblatt, JM, Huffman, LC & Reiss, AL (1994) Folic-acid in neurodevelopment and child-psychiatry. Prog Neuropsychopharmacol Biol Psychiatry 18, 647660.
34. Schaevitz, L, Berger-Sweeney, J & Ricceri, L (2014) One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. Neurosci Biobehav Rev 46, 270284.
35. Braun, JM, Froehlich, T, Kalkbrenner, A, et al. (2014) Brief report: are autistic-behaviors in children related to prenatal vitamin use and maternal whole blood folate concentrations? J Autism Dev Disord 44, 26022607.
36. Steenweg-de Graaff, J, Ghassabian, A, Jaddoe, VW, et al. (2015) Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. Eur J Public Health 25, 431433.
37. Roth, C, Magnus, P, Schjolberg, S, et al. (2011) Folic acid supplements in pregnancy and severe language delay in children. JAMA 306, 15661573.
38. Julvez, J, Fortuny, J, Mendez, M, et al. (2009) Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. Paediatr Perinat Epidemiol 23, 199206.
39. Wehby, GL & Murray, JC (2008) The effects of prenatal use of folic acid and other dietary supplements on early child development. Matern Child Health J 12, 180187.
40. Veena, SR, Krishnaveni, GV, Srinivasan, K, et al. (2010) 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 140, 10141022.
41. Christian, P, Murray-Kolb, LE, Khatry, SK, et al. (2010) Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. J Am Med 304, 27162723.
42. Dobo, M & Czeizel, A (1998) Long-term somatic and mental development of children after periconceptional multivitamin supplementation. Eur J Pediatr 157, 719723.
43. Division of Birth Defects – National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (2013) Autism spectrum disorders data & statistics. (accessed 15 October 2013).
44. Lawlor, DA, Davey Smith, G, Kundu, D, et al. (2004) Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 363, 17241727.
45. Pouchieu, C, Levy, R, Faure, C, et al. (2013) Socioeconomic, lifestyle and dietary factors associated with dietary supplement use during pregnancy. PLoS ONE 8, e70733.
46. Tinker, SC, Hamner, HC, Berry, RJ, et al. (2012) Does obesity modify the association of supplemental folic acid with folate status among nonpregnant women of childbearing age in the United States? Birth Defects Res A Clin Mol Teratol 94, 749755.
47. Avalos, LA, Kaskutas, LA, Block, G, et al. (2009) Do multivitamin supplements modify the relationship between prenatal alcohol intake and miscarriage? Am J Obstet Gynecol 201, 563.e1563.e9.
48. Wu, TJ, Buck, G & Mendola, P (1998) Can regular multivitamin/mineral supplementation modify the relation between maternal smoking and select adverse birth outcomes? Ann Epidemiol 8, 175183.
49. Bjorke-Monsen, AL, Roth, C, Magnus, P, et al. (2013) Maternal B vitamin status in pregnancy week 18 according to reported use of folic acid supplements. Mol Nutr Food Res 57, 645652.
50. Schmidt, RJ, Tancredi, DJ, Krakowiak, P, et al. (2014) Maternal intake of supplemental iron and risk of autism spectrum disorder. Am J Epidemiol 180, 890900.
51. Lyall, K, Munger, KL, O’Reilly, ÉJ, et al. (2013) Maternal dietary fat intake in association with autism spectrum disorders. Am J Epidemiol 178, 209220.
52. Steenweg-de Graaff, J, Roza, SJ, Steegers, EA, et al. (2012) Maternal folate status in early pregnancy and child emotional and behavioral problems: the Generation R Study. Am J Clin Nutr 95, 14131421.
53. Schlotz, W, Jones, A, Phillips, DI, et al. (2010) Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring. J Child Psychol Psychiatry 51, 594602.
54. McNulty, B, Pentieva, K, Marshall, B, et al. (2011) Women’s compliance with current folic acid recommendations and achievement of optimal vitamin status for preventing neural tube defects editorial comment. Obstet Gynecol Surv 66, 541542.
55. Brough, L, Rees, GA, Crawford, MA, et al. (2009) Social and ethnic differences in folic acid use preconception and during early pregnancy in the UK: effect on maternal folate status. J Hum Nutr Diet 22, 100107.
56. Pietruszka, B & Brzozowska, A (2006) Folic acid supplementation practice in Europe – plenary lecture. Pol J Food Nutr Sci 15/56, 9399.
57. Sadler, TW (2011) Langman’s Medical Embryology. Philadelphia: Lippincott Williams & Wilkins.
58. Ghishan, FK, Said, HM, Wilson, PC, et al. (1986) Intestinal transport of zinc and folic-acid – a mutual inhibitory effect. Am J Clin Nutr 43, 258262.
59. Milne, DB, Canfield, WK, Mahalko, JR, et al. (1984) Effect of oral folic-acid supplements on zinc, copper, and iron-absorption and excretion. Am J Clin Nutr 39, 535539.
60. Anonymous (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 41, 1–7.
61. Lawrence, JM, Bpetitti, D, Watkins, M, et al. (1999) Trends in serum folate after food fortification. Lancet 354, 915916.
62. King, M & Bearman, P (2009) Diagnostic change and the increased prevalence of autism. Int J Epidemiol 38, 12241234.
63. Shattuck, PT (2006) The contribution of diagnostic substitution to the growing administrative prevalence of autism in US special education. Pediatrics 117, 10281037.
64. Liu, K-Y, King, M & Bearman, PS (2010) Social influence and the autism epidemic. Am J Soc 115, 13871434.
65. Liu, K, Zerubavel, N & Bearman, P (2010) Social demographic change and autism. Demography 47, 327343.
66. King, MD, Fountain, C, Dakhlallah, D et al. (2009) Estimated autism risk and older reproductive age. Am J Public Health 99, 16731679.
67. Rogers, EJ (2008) Has enhanced folate status during pregnancy altered natural selection and possibly autism prevalence? A closer look at a possible link. Med Hypotheses 71, 406410.
68. Mayor-Olea, A, Callejon, G, Palomares, AR, et al. (2008) Human genetic selection on the MTHFR 677C>T polymorphism. BMC Med Genet 9, 104.
69. Guo, T, Chen, H, Liu, B, et al. (2012) Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genet Test Mol Biomarkers 16, 968973.
70. Boris, M, Goldblatt, A, Galanko, J, et al. (2004) Association of MTHFR gene variants with autism. J Am Physicians Surg 9, 106108.
71. Black, MM (2008) Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 29, S126S131.
72. Kalmbach, RD, Choumenkovitch, SF, Troen, AP, et al. (2008) A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate. J Nutr 138, 23232327.
73. Schirch, L & Peterson, D (1980) Purification and properties of mitochondrial serine hydroxymethyltransferase. J Biol Chem 255, 78017806.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed