Folic acid versus 5- methyl tetrahydrofolate supplementation in pregnancy

Eur J Obstet Gynecol Reprod Biol. 2020 Oct:253:312-319. doi: 10.1016/j.ejogrb.2020.06.012. Epub 2020 Jun 13.


Folate (vitamin B9) is widely accepted to protect against fetal neural tube defects. The main sources of dietary folate are folic acid-fortified foods and folic acid-containing dietary supplements. However, folic acid is inactive in the human body and must be converted by the liver into the active molecule 5-methyltetrahydrofolate (5-MTHF). 5-MTHF functions as a methyl donor in many metabolic reactions, including the conversion of homocysteine into methionine, the biosynthesis of glycine from serine, and the biosynthesis of DNA precursor molecules. Therefore, folate is fundamental for growth, especially in the embryonic and fetal stages. Prescription of folic acid to women in the preconception period and during pregnancy is a consolidated practice. However, it can pose health risks in certain conditions, such as megaloblastic anemia, where it will conceal megaloblastic anemia due to vitamin B12 deficiency and in cases of reduced hepatic transformation of folic acid (e.g. due to genetic variants or during some pharmacotherapies). Some of these risks can be avoided by supplementation with 5-MTHF rather than folic acid. Because 5-MTHF does not require activation, it is immediately available to mother and fetus and does not accumulate in blood like folic acid does in cases of reduced hepatic transformation. This paper reviews the advantages and disadvantages of folate supplementation with folic acid versus 5-MTHF, with a focus on maternal and fetal health.

Keywords: Hyperhomocysteinemia; Methyltetrahydrofolate reductase; Neural tube defect; Placenta; Pre-eclampsia; Vitamin B9.

Publication types

  • Review

MeSH terms

  • Dietary Supplements
  • Female
  • Folic Acid*
  • Humans
  • Neural Tube Defects* / prevention & control
  • Pregnancy
  • Tetrahydrofolates


  • Tetrahydrofolates
  • Folic Acid
  • 5-methyltetrahydrofolate