5000 mcg Folic Acid Reduces Fertility

This week I wanted to diverge on subjects a bit just because a very relevant question came up in the MTHFR community, This is such an important issue that I want to make sure it gets the attention it deserves.

One of our members is pregnant and her midwife is recommending 5000 mcg folic acid in spite of her MTHFR issue.  This is a common question because 5000 mcg folic acid is standard practice in many fertility centers and medical offices for low fertility to help women get pregnant, or for pregnancies that are considered at risk.

Like everything else involving MTHFR, research is limited, but I do want to deep dive into a couple of relevant studies.

5000 mcg Folic Acid Reduces Fertility and 600 mcg L-5MTHF Boosts Fertility

The most important piece of research to take to your midwife or fertility practitioner is a study published in the Journal of Assisted Reproduction and Genetics in 2018, showing that 5000 mcg folic acid reduces fertility, while 600 mcg L-5MTHF boosts fertility.

This study followed 33 couples in which one or both of the partners had an MTHR polymorphism who had fertility problems lasting at least 4 years.  This could include recurrent fetal loss, premature ovarian failure, or abnormal sperm parameters - so bear in mind this could be the mother or the father who has MTHFR issues. Two-thirds of these couples had previously failed assisted reproductive technology attempts.

Most of the women in this study had been previously treated, unsuccessfully, with 5000 mcg (or 5 mg) folic acid.

The couples in this study were given 600 mcg 5-LMTH, which is the active form of folate, for four months before attempting conception or starting another round of assisted fertility treatment. This four-month period was chosen to allow for a complete cycle of spermatogenesis, which is approximately 74 days.

The results of this one simple intervention were, in my opinion, absolutely astounding. Of the 33 couples:

• 2 were still in treatment at the date of reporting.

• 13 couples conceived spontaneously (this is after four years of unsuccessful reproductive attempts)

• 14 achieved successful pregnancies using ART (assisted reproductive technology). ART typically refers to IVF or in-vitro fertilization. 

• 3 couples did not achieve successful pregnancies.

• 1 couple failed to report back.

I am going to read the conclusion of this research article verbatim because frankly, I couldn't sum it up better.

Unmetabolized Folic Acid Causes Pseudo-MTHFR

The other issue considered here is something called Unmetabolized Folic Acid Syndrome, which has been demonstrated in  "wild type" people to cause pseudo-MTHFR. In pseudo-MTHFR, people who have fully functioning MTHFR enzymes develop both high levels of unmetabolized folic acid and high levels of homocysteine in their blood. In people with an MTHFR deficiency, UMFA blocks the entry of folates into the folate cycle and further impairs the capacity of their already struggling MTHFR enzymes.

Unmetabolized Folic Acid has also been implicated in promoting colorectal and prostate cancer. And folic acid itself shows poor clinical success, and in some cases, it tests worse than a placebo in reducing homocysteine levels or downstream measures of cardiac health.

5 mg Folic Acid May Cause Negative Pregnancy Outcomes

A group of children of MTHFR-carrying hypo-fertile parents was observed in this study. The children were at ages after breastfeeding stopped and before puberty began, generally from 2 - 6 years old. Some of the parents of these children took L-5MTHF during pregnancy and nursing at the advice of a fertility clinic, and some took the US standard-of-care, which is 5 mg folic acid.

In the study were the children of 21 couples treated with folic acid, and the children of 36 couples treated with L-5MTHF.

In the folic-acid treated group the following complications were noted:

• 2 children were diagnosed with autism spectrum disorder (ASD)

• 1 child had high circulating levels of homocysteine

• 1 child was affected by oculo-auriculo-vertebral spectrum (OAVS), a syndrome known to be linked to DNA methylation

In the L-5MTHF (methyl folate) treated group:

• No pathology of any kind was detected in these children.

Given that the methyl folate group was larger, it stands to reason that there should be more cases of autism, more children with high homocysteine, and more pathology, but instead we see none. That is very telling in my opinion.

Preconception and fertility work are vulnerable and time-sensitive, so please understand the issues at hand and work closely with your OB-GYN or Midwife. The links to the relevant articles are below - I highly recommend printing out the full articles and taking them to your OB-GYN or Midwife's Office.

References:

Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. Journal of Assisted Reproduction and Genetics. 2018 Aug;35(8):1431-1435. doi: 10.1007/s10815-018-1225-2. Epub 2018 Jun 7. PMID: 29882091; PMCID: PMC6086798.

Christensen KE, Mikael LG, Leung KY, Lévesque N, Deng L, Wu Q, Malysheva OV, Best A, Caudill MA, Greene ND, Rozen R. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. American Journal of Clinical Nutrition 2015 Mar;101(3):646-58. doi: 10.3945/ajcn.114.086603. Epub 2015 Jan 7. PMID: 25733650; PMCID: PMC4340065.

Miraglia N, Dehay E. Folate Supplementation in Fertility and Pregnancy: The Advantages of (6S)5-Methyltetrahydrofolate. Alternative Therapies in Health and Medicine 2022 May;28(4):12-17. PMID: 35653630.

Clement A, Viot G, Elder K, Clement P, Menezo YJR. Can some metabolic one-carbon cycle linked diseases be prevented? The impact of treating hypo-fertile couples carrying MTHFR SNPs with folic acid and 5-MTHF on outcomes in the offspring: a case retrospective series. Journal of Assisted Reproduction and Genetics. 2025 Feb;42(2):533-539. doi: 10.1007/s10815-024-03343-y. Epub 2024 Dec 11. PMID: 39658735; PMCID: PMC11871243.