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 Sep;15(9):1728-36. doi: 10.1017/S1368980012000067. Epub 2012 Feb 8.


Objective: To investigate whether high doses of folic acid supplementation in early pregnancy are associated with child neurodevelopment at 18 months of age.

Design: The study uses data from the prospective mother-child cohort 'Rhea' study. Pregnant women completed an interviewer-administered questionnaire on folic acid supplementation at 14-18 weeks of gestation. Neurodevelopment at 18 months was assessed with the use of the Bayley Scales of Infant and Toddler Development (3rd edition). Red-blood-cell folate concentrations in cord blood were measured in a sub-sample of the study population (n 58).

Setting: Heraklion, Crete, Greece, 2007-2010.

Subjects: Five hundred and fifty-three mother-child pairs participating in the 'Rhea' cohort.

Results: Sixty-eight per cent of the study participants reported high doses of supplemental folic acid use (5 mg/d), while 24 % reported excessive doses of folic acid (>5 mg/d) in early pregnancy. Compared with non-users, daily intake of 5 mg supplemental folic acid was associated with a 5-unit increase on the scale of receptive communication and a 3·5-unit increase on the scale of expressive communication. Doses of folic acid supplementation higher than 5 mg/d were not associated with additional increase in the neurodevelopmental scales.

Conclusions: This is the first prospective study showing that high doses of supplementary folic acid in early pregnancy may be associated with enhanced vocabulary development, communicational skills and verbal comprehension at 18 months of age. Additional longitudinal studies and trials are needed to confirm these results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child Development / drug effects*
  • Cohort Studies
  • Dietary Supplements*
  • Dose-Response Relationship, Drug*
  • Female
  • Folic Acid / administration & dosage*
  • Greece / epidemiology
  • Humans
  • Infant
  • Male
  • Mothers / education
  • Neurons / drug effects*
  • Neurons / metabolism
  • Prospective Studies
  • Reproducibility of Results
  • Socioeconomic Factors
  • Young Adult


  • Folic Acid