MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series

J Assist Reprod Genet. 2018 Aug;35(8):1431-1435. doi: 10.1007/s10815-018-1225-2. Epub 2018 Jun 7.


Purpose: To evaluate the possibility of correcting metabolic defects in gametes and embryos due to methylene tetra hydrofolate reductase (MTHFR) isoforms C677T and A1298C, by supplementation with 5-methyl THF instead of synthetic folic acid. In these couples, high doses of folic acid lead to UMFA (un-metabolized folic acid) syndrome.

Methods: Thirty couples with fertility problems lasting for at least 4 years, such as recurrent fetal loss, premature ovarian insufficiency, or abnormal sperm parameters, with two thirds of them having failed assisted reproductive technology (ART) attempts were included in this program. For all couples, at least one of the partners was a carrier of one of the two main MTHFR isoforms. Most of the women had been previously treated unsuccessfully with high doses of folic acid (5 mg/day), according to what is currently proposed in the literature. The couples carrying one of the isoforms were treated for 4 months with 5-MTHF, at a dose of 600 micrograms per day, before attempting conception or starting another attempt at ART. The duration of treatment corresponding to an entire cycle of spermatogenesis is approximately 74 days.

Results: In this first series of 33 couples, one couple was not followed-up, and two are still currently under treatment. No adverse effects were observed. Thirteen of the couples conceived spontaneously, the rest needing ART treatment in order to achieve pregnancy. Only three couples have, so far, not succeeded.

Conclusion: The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100-200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).

Keywords: 5-MTHF; Embryos; Folic acid; Gametes; MTHFR; Miscarriages; UMFA.

MeSH terms

  • Adult
  • Dietary Supplements / adverse effects
  • Dose-Response Relationship, Drug
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / metabolism
  • Humans
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Pregnancy
  • Pregnancy Outcome
  • Protein Isoforms / genetics*
  • Reproductive Techniques, Assisted*
  • Spermatogenesis / drug effects
  • Tetrahydrofolates / administration & dosage*


  • Protein Isoforms
  • Tetrahydrofolates
  • Folic Acid
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-methyltetrahydrofolate