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Maternal folate levels during pregnancy and children’s neuropsychological development at 2 years of age



To explore the relationship between maternal folate levels during pregnancy and children’s neuropsychological development at 2 years of age.


In the birth cohort MKFOAD, maternal serum folate concentrations at 12–14, 22–26, and 34–36 weeks of gestation were measured, as well as red blood cell (RBC) folate at 12–14 weeks. Neurodevelopment of 2-year-old children was assessed by Gesell Development Scale (GDS), which contained subscales of gross motor, fine motor, language, adaptive behavior, and social behavior. Linear regression models were applied to investigate the association of maternal folate levels with children’s developmental quotients (DQs).


One hundred and eighty singleton children participated the GDS assessment, of whom 97 (53.9%) were boys. Median RBC folate concentration was 1002.8 (IQR = 577.6) nmol L−1 in early pregnancy and median serum folate concentrations were, respectively, 33.9 (IQR = 9.2) nmol L−1, 26.3 (IQR = 14.3) nmol L−1, and 26.7 (IQR = 18.9) nmol L−1. Maternal serum folate concentration in late pregnancy was significantly associated with children’s language development, where language DQ increases by 3.1 (95% CI 0.6, 5.5) for every 10 nmol L−1 increment of serum folate concentration. And maternal serum folate in early pregnancy was significantly associated with children’s fine motor development, with 2.0 (95% CI 0.1, 4.0) DQ decrease for 10 nmol L−1 increase of serum folate.


Maternal serum folate in late pregnancy was significantly associated with children’s language development at age 2, which supports the importance of remaining folic acid supplementation across the entire gestation. However, maternal serum folate in early pregnancy was also inversely associated with children’s fine motor development.

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Fig. 1: Flow diagram of subject selection.
Fig. 2: Distribution of maternal serum folate at early, mid, and late pregnancy and RBC folate at early pregnancy.

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  1. Wallingford JB, Niswander LA, Shaw GM, Finnell RH. The continuing challenge of understanding, preventing, and treating neural tube defects. Science. 2013;339:1222002.

    Article  Google Scholar 

  2. Gueant JL, Namour F, Gueant-Rodriguez RM, Daval JL. Folate and fetal programming: a play in epigenomics? Trends Endocrinol Metab. 2013;24:279–89.

    Article  CAS  Google Scholar 

  3. Temel S, Erdem O, Voorham TA, Bonsel GJ, Steegers EA, Denktas S. Knowledge on preconceptional folic acid supplementation and intention to seek for preconception care among men and women in an urban city: a population-based cross-sectional study. BMC Pregnancy Childbirth. 2015;15:340.

    Article  Google Scholar 

  4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131–7.

    Article  Google Scholar 

  5. 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;341:1485–90.

    Article  CAS  Google Scholar 

  6. Force USPST, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, et al. Folic acid supplementation for the prevention of neural tube defects: US preventive services task force recommendation statement. JAMA. 2017;317:183–9.

    Article  Google Scholar 

  7. Forns J, Aranbarri A, Grellier J, Julvez J, Vrijheid M, Sunyer J. A conceptual framework in the study of neuropsychological development in epidemiological studies. Neuroepidemiology. 2012;38:203–8.

    Article  CAS  Google Scholar 

  8. 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;134:162–6.

    Article  CAS  Google Scholar 

  9. 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;15:1–9.

    Article  Google Scholar 

  10. Husebye ESN, Gilhus NE, Riedel B, Spigset O, Daltveit AK, Bjork MH. Verbal abilities in children of mothers with epilepsy: Association to maternal folate status. Neurology. 2018;91:e811–21.

    Article  Google Scholar 

  11. Julvez J, Fortuny J, Mendez M, Torrent M, Ribas-Fito 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;23:199–206.

    Article  Google Scholar 

  12. Roth C, Magnus P, Schjolberg S, Stoltenberg C, Suren P, McKeague IW, et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA. 2011;306:1566–73.

    Article  CAS  Google Scholar 

  13. Yan J, Zhu Y, Cao LJ, Liu YY, Zheng YZ, Li W, et al. Effects of maternal folic acid supplementation during pregnancy on infant neurodevelopment at 1 month of age: a birth cohort study in China. Eur J Nutr. 2019. E-pub ahead of print.

  14. 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;26:328–35.

    Article  Google Scholar 

  15. Ars CL, Nijs IM, Marroun HE, Muetzel R, Schmidt M, Steenweg-de Graaff J, et al. Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study. Br J Nutr. 2016;122:S1–9.

    Article  Google Scholar 

  16. Bhate VK, Joshi SM, Ladkat RS, Deshmukh US, Lubree HG, Katre PA, et al. Vitamin B12 and folate during pregnancy and offspring motor, mental and social development at 2 years of age. J Dev Orig Health Dis. 2012;3:123–30.

    Article  CAS  Google Scholar 

  17. Tamura T, Goldenberg RL, Chapman VR, Johnston KE, Ramey SL, Nelson KG. Folate status of mothers during pregnancy and mental and psychomotor development of their children at five years of age. Pediatrics. 2005;116:703–8.

    Article  Google Scholar 

  18. 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;140:1014–22.

    Article  CAS  Google Scholar 

  19. Yang YF. Rating scales for children’s developmental behavior and mental health. Beijing: People’s Medical Publishing House; 2016.

  20. McDonald JH. Handbook of Biological Statistics. 3rd ed. Baltimore, Maryland: Sparky House Publishing; 2014.

  21. Team RC. R: A language and environment for statistical computing; 2013.

  22. 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;64:421–3.

    Google Scholar 

  23. Zhou L, Xu J, Zhang J, Yan C, Lin Y, Jia Y, et al. Prenatal maternal stress in relation to the effects of prenatal lead exposure on toddler cognitive development. Neurotoxicology. 2017;59:71–8.

    Article  CAS  Google Scholar 

  24. Geoffroy A, Kerek R, Pourie G, Helle D, Gueant JL, Daval JL, et al. Late maternal folate supplementation rescues from methyl donor deficiency-associated brain defects by restoring Let-7 and miR-34 pathways. Mol Neurobiol. 2017;54:5017–33.

    Article  CAS  Google Scholar 

  25. Caffrey A, Irwin RE, McNulty H, Strain JJ, Lees-Murdock DJ, McNulty BA, 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;107:566–75.

    Article  Google Scholar 

  26. Roth TL, Sweatt JD. Epigenetic marking of the BDNF gene by early-life adverse experiences. Horm Behav. 2011;59:315–20.

    Article  CAS  Google Scholar 

  27. Jing Y. Effects of Folic Acid Supplementation during Pregnancy on the Neurodevelopment of Infants by Inflammatory Mechanism:A Birth Cohort Study [PhD]. Tianjin: Medical University; 2018.

    Google Scholar 

  28. WHO. Daily iron and folic acid supplementation during pregnancy. WHO. http://www.whoint/elena/titles/guidance_summaries/daily_iron_pregnancy/en. Accessed 24 Jan 2016.

  29. Anderson CA, Beresford SA, McLerran D, Lampe JW, Deeb S, Feng Z, 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;57:637–44.

    Article  CAS  Google Scholar 

  30. Cabrera RM, Souder JP, Steele JW, Yeo L, Tukeman G, Gorelick DA, et al. The antagonism of folate receptor by dolutegravir: developmental toxicity reduction by supplemental folic acid. AIDS. 2019;33:1967–76.

    Article  CAS  Google Scholar 

  31. Li Q, Zhang Y, Huang L, Zhong C, Chen R, Zhou X, et al. High-dose folic acid supplement use from prepregnancy through midpregnancy is associated with increased risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care. 2019;42:e113–5.

    Article  CAS  Google Scholar 

  32. Valera-Gran D, Garcia de la Hera M, Navarrete-Munoz EM, Fernandez-Somoano A, Tardon A, Julvez J, et al. Folic acid supplements during pregnancy and child psychomotor development after the first year of life. JAMA Pediatr. 2014;168:e142611.

    Article  Google Scholar 

  33. Valera-Gran D, Navarrete-Munoz EM, Garcia de la Hera M, Fernandez-Somoano A, Tardon A, Ibarluzea J, 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;106:878–87.

    CAS  Google Scholar 

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The authors gratefully thank all of the participants in this study and Minhang Maternal and Child Health Hospital for supporting this study.


This work was supported by National key research and development program (Grant No: 2016YFC1000500), Shanghai Public Health Three-Year Action Plan (Grant No:2015–82), and Canada-China Clinical Research program (Grant No: 201607).

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XYH and YY acquired data, analyzed the data, drafted and revised the manuscript. YL and YingZ acquired data and revised the manuscript, YiZ, XTC, YJ, and LHW played an important role in interpreting the results and revised the manuscript. WLY conceived and designed the work, revised the manuscript and made final approval of the work. All authors approved the final version and agree to be fully accountable for ensuring the integrity and accuracy of the work.

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Correspondence to Weili Yan.

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Huang, X., Ye, Y., Li, Y. et al. Maternal folate levels during pregnancy and children’s neuropsychological development at 2 years of age. Eur J Clin Nutr 74, 1585–1593 (2020).

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