Skip to main content Accessibility help

Moderately elevated preconception fasting plasma total homocysteine is a risk factor for psychological problems in childhood

  • Joana Roigé-Castellví (a1) (a2), Michelle Murphy (a3) (a4), Joan Fernández-Ballart (a3) (a4) and Josefa Canals (a1) (a2)



We investigated the effect of maternal preconception fasting plasma total homocysteine (tHcy) on psychological problems in children aged 6 years from normal pregnancies.


A longitudinal study was carried out from preconception, throughout each trimester of pregnancy, until 6 years of age in the offspring. Fasting blood samples at 2–10 weeks preconception and non-fasting samples at birth were collected. Parents completed the Child Behaviour Checklist (CBCL) and teachers the Inattention-Overactivity with Aggression (IOWA) scale for the 6-year-old children.


Elevated tHcy during pregnancy has been associated with several adverse outcomes and with neurodevelopmental impairment in the offspring.


The initial sample consisted of 139 healthy non-pregnant women who were planning on becoming pregnant. Eighty-one mother–child dyads were followed from preconception until 6 years of age.


After adjusting for covariables, multiple linear regression models showed that higher preconception tHcy was associated with higher scores in internalizing dimension (β=0·289; P=0.028), specifically in withdrawn behaviour (β=0·349; P=0·009), anxiety/depression (β=0·303; P=0·019) and social problems (β=0·372; P=0·009). Aggressive behaviour in the school setting was higher in children whose mothers had higher preconception tHcy (β=0·351; P=0·014).


Moderately elevated preconception tHcy may increase the risk of psychological problems in offspring during childhood. These findings add to the evidence that maternal nutritional status, even before being pregnant, can affect later offspring health and may be important to consider when developing future public health policy.


Corresponding author

*Corresponding author: Email


Hide All
1. Kalhan, SC (2016) One carbon metabolism in pregnancy: impact on maternal, fetal and neonatal health. Mol Cell Endocrinol 435, 4860.
2. Selhub, J (2008) Public health significance of elevated homocysteine. Food Nutr Bull 29, 116125.
3. Brustolin, S, Giugliani, R & Félix, TM (2010) Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res 43, 17.
4. Douaud, G, Refsum, H, de Jager, C et al. (2013) Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 110, 95239528.
5. Haan, MN, Miller, JW, Aiello, AE et al. (2007) Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr 85, 511517.
6. Mattson, MP & Shea, TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26, 137146.
7. Seshadri, S, Beiser, A, Selhub, J et al. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346, 476483.
8. Tang, K-F, Li, Y-L & Wang, H-Y (2015) Quantitative assessment of maternal biomarkers related to one-carbon metabolism and neural tube defects. Sci Rep 5, 8510.
9. Bergen, NE, Jaddoe, VW, Timmermans, S et al. (2012) Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG 119, 739751.
10. Murphy, MM, Scott, JM, Arija, V et al. (2004) Maternal homocysteine before conception and throughout pregnancy predicts fetal homocysteine and birth weight. Clin Chem 50, 14061412.
11. Verkleij-Hagoort, A, Bliek, J, Sayed-Tabatabaei, F et al. (2007) Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am J Med Genet A 143A, 952960.
12. Berti, C, Biesalski, HK, Gärtner, R et al. (2011) Micronutrients in pregnancy: current knowledge and unresolved questions. Clin Nutr 30, 689701.
13. Blumfield, ML, Hure, AJ, Macdonald-wicks, L et al. (2013) Micronutrient intakes during pregnancy in developed countries: systematic review and meta-analysis. Nutr Rev 71, 118132.
14. Murphy, MM, Scott, JM, McPartlin, JM et al. (2002) The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study. Am J Clin Nutr 76, 614619.
15. McNulty, B, McNulty, H, Marshall, B et al. (2013) Impact of continuing folic acid after the first trimester of pregnancy: findings of a randomized trial of folic acid supplementation in the second and third trimesters. Am J Clin Nutr 98, 9298.
16. Murphy, MM, Fernandez-Ballart, JD, Molloy, AM et al. (2017) Moderately elevated maternal homocysteine at preconception is inversely associated with cognitive performance in children 4 months and 6 years after birth. Matern Child Nutr 13, e12289.
17. Ars, CL, Nijs, IM, Marroun, HE, et al. (2016) Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study. Br J Nutr. Published online: 22 January 2016. doi: 10.1017/S0007114515002081.
18. Anjos, T, Altmäe, S, Emmett, P et al. (2013) Nutrition and neurodevelopment in children: Focus on NUTRIMENTHE project. Eur J Nutr 52, 18251842.
19. Schlotz, W, Jones, A, Phillips, DIW 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.
20. Roza, SJ, van Batenburg-Eddes, T, Steegers, E a P et al. (2010) Maternal folic acid supplement use in early pregnancy and child behavioural problems: the Generation R Study. Br J Nutr 103, 445452.
21. DeVilbiss, EA, Gardner, RM, Newschaffer, CJ et al. (2015) Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr 114, 663672.
22. Schmidt, RJ, Tancredi, DJ, Ozonoff, S et al. (2012) Maternal periconceptional folic acid intake and risk for developmental delay and autism spectrum disorder: a case–control study. Am J Clin Nutr 96, 8089.
23. Surén, 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.
24. Virk, J, Liew, Z, Olsen, J et al. (2015) Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism 20, 710718.
25. Boyles, AL, Yetley, EA, Thayer, KA et al. (2016) Safe use of high intakes of folic acid: research challenges and paths forward. Nutr Rev 74, 469474.
26. Valera-Gran, D, Navarrete-Muñoz, EM, Garcia de la Hera, M et al. (2017) Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4–5 years of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr 106, 878887.
27. Selhub, J & Rosenberg, IH (2016) Excessive folic acid intake and relation to adverse health outcome. Biochimie 126, 7178.
28. Bueno, O, Molloy, AM, Fernandez-Ballart, JD et al. (2016) Common polymorphisms that affect folate transport or metabolism modify the effect of the MTHFR 677C>T polymorphism on folate status. J Nutr 146, 18.
29. Canals, J, Esparó, G & Fernandez-Ballart, J (2006) Neonatal behaviour characteristics and psychological problems at 6 years. Acta Paediatr 95, 14121417.
30. Achenbach, TM (1991) Manual for the Child Behavior Checklist (4–18 and 1991 profile). Burlington, VT: University of Vermont.
31. Loney, J & Milich, R (1982) Hyperactivity, inattention and aggression in clinical practice. Adv Dev Behav Pediatr 3, 113232.
32. Spielberger, CD, Gorsuch, RL & Lushene, RE (1988) Cuestionario de Ansiedad Estado-Rasgo. Manual de Adaptación Española. Madrid: TEA Ediciones.
33. Wechsler, D (1996) Escala de Inteligencia de Wechsler para Preescolar y Primaria, WIPPSI. Manual de Adaptación Española. Madrid: TEA Ediciones.
34. Murphy, MM, Vilella, E, Ceruelo, S et al. (2002) The MTHFR C677T, APOE, and PON55 gene polymorphisms show relevant interactions with cardiovascular risk factors. Clin Chem 48, 372375.
35. Belinson, H, Nakatani, J, Babineau, BA et al. (2016) Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors. Mol Psychiatry 21, 14171433.
36. Wang, M, Li, K, Zhao, D et al. (2017) The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Mol Autism 8, 51.
37. Raghavan, R, Riley, AW, Volk, H et al. (2017) Maternal multivitamin intake, plasma folate and vitamin B12 levels and autism spectrum disorder risk in offspring. Paediatr Perinat Epidemiol 32, 100111.
38. Strøm, M, Granström, C, Lyall, K et al. (2017) Research letter: Folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder. Psychol Med 48, 10481054.
39. DeVilbiss, EA, Magnusson, C, Gardner, RM, et al. (2017) Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study. BMJ 4273, j4273.
40. Zhou, J, Liu, A, He, F et al. (2018) High prevalence of serum folate receptor autoantibodies in children with autism spectrum disorders. Biomarkers 23, 622624.
41. 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.
42. 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 9–10 year old children in South-India. J Nutr 140, 10141022.
43. Tamura, T, Goldenberg, RL, Chapman, VR et al. (2005) Folate status of mothers during pregnancy and mental and psychomotor development of their children at five years of age. Pediatrics 116, 703708.
44. Glover, V (2018) Stress in pregnancy can change fetal and child development. In Transforming Infant Wellbeing: Research, Policy and Practice for the First 1001 Critical Days, pp. 98106 [P Leach, editor]. Abingdon: Routledge.



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