Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 8, pp 1431–1435 | Cite as

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

  • Edouard J. Servy
  • Laetitia Jacquesson-Fournols
  • Marc Cohen
  • Yves J. R. MenezoEmail author
Gamete Biology



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.


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.


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.


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).


MTHFR Gametes Embryos Miscarriages Folic acid 5-MTHF UMFA 


Authors’ contributions

Edouard J Servy, MD, FACOG, followed clinically the patients and collected the data.

Laetitia Jacquesson-Fournols, MD, Endocrinologist,, followed clinically the patients and collected the data.

Marc Cohen MD, Obst Gyn, follows clinically the patients and collected the data.

Yves J R Menezo, PhD, Dr. Sci, FRSM, Senior Clinical Embryologist (ESHRE) (*corresponding author) controlled dosages designed the protocol and wrote the paper.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest except MC who is dealing with a company saling Neutraceuticals.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Servy Institute of Reproductive EndocrinologyAugustaUSA
  2. 2.Cabinet d endocrinologieParisFrance
  3. 3.Clinique NateciaLyonFrance
  4. 4.Laboratoire ClementParisFrance
  5. 5.London Fertility AssociatesLondonUK

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