MTHFR Polymorphisms and Fertility
Svetlana Mortensen
MD, Functional & Integrative Medicine • 14 min read
What is MTHFR?
MTHFR polymorphisms (genetic variants) are found in more than 60–80% of the population, and many women with these variants conceive and carry pregnancies completely normally. That is precisely why there is still debate among reproductive specialists over whether this genetic factor should be actively considered and addressed.
At the same time, MTHFR polymorphisms may coexist with other polymorphisms, hormonal imbalances, nutrient deficiencies, and environmental influences that can contribute to fertility problems and pregnancy loss — including recurrent loss.
MTHFR stands for methylenetetrahydrofolate reductase — an enzyme that helps convert folate into methylfolate and produces methyl-group donors (CH₃) for the major biochemical pathway known as methylation. Because MTHFR is the slowest enzyme in this broader process, variants that reduce its function may compromise the entire pathway.
This process also includes the conversion of the amino acid homocysteine into methionine. In excess, homocysteine is toxic — and only relatively recently have pregnant women begun to be tested for it, a step still not standard-of-care in many countries.
The Methylation Pathway
Methylation is a critically important biochemical process in which methyl groups (CH₃) are used across virtually every system in the body. MTHFR is also involved in the production of the key methyl donor S-adenosylmethionine (SAMe).
Methylation is required for
PCOS & Homocysteine
Women with PCOS often have elevated homocysteine, which has been linked to the insulin resistance and increased androgen levels that commonly accompany the condition. High-sensitivity C-reactive protein, homocysteine, and adiponectin are frequently abnormal in women with PCOS — possible determinants include insulin resistance and hyperandrogenism.
More specifically, the MTHFR enzyme converts folate — 5,10-methylenetetrahydrofolate — into 5-methyltetrahydrofolate. This active methylated form is what is available in quality supplementation.
How Does MTHFR Affect Fertility?
There are two major variants of the gene encoding the MTHFR enzyme:
C677T
Reduces enzyme activity by ~70%. Clearly associated with male infertility. Associated with premature ovarian insufficiency, higher baseline FSH, and requires greater FSH stimulation during IVF.
A1298C
Reduces enzyme activity by ~40%. Associated with fewer retrieved oocytes, lower chances of successful pregnancy after IVF, and recurrent implantation failure when combined with C677T.
Genetic polymorphisms do not diagnose deficiencies.They indicate predisposition. Once deficiencies develop, diagnoses may follow — but conception and pregnancy are especially sensitive to even “mild” deficiencies.
A woman who doesn't eat leafy greens, asparagus, beets, broccoli, organ meats, or legumes can enter a deficient state quite easily. A woman with MTHFR polymorphisms may do so even faster. For some combinations of folate-cycle polymorphisms, diet alone is often not enough — they may require supplementation in active forms.
For the C677T mutation, folate should not be given as folic acid. Due to the genetic predisposition, it will not be effectively converted into the active form — and may instead contribute to elevated homocysteine. For methylation, folic acid is like putting square wheels on a car.
The usual dose of folate as 5-MTHF for women with heterozygous or homozygous variants is 5,000–10,000 mcg per day.
The Thrombosis Cascade
Oocyte Quality, Embryo Quality & Ovarian Reserve
Laanpere et al. (2010)
“Poor folate status disrupts methylation and DNA integrity and raises blood homocysteine levels. Elevated homocysteine levels in follicular fluid correlate with oocyte immaturity and poor early embryo quality, while MTHFR gene polymorphisms are associated with lower ovarian reserve, reduced response to follicular stimulation, and lower chances of live birth after IVF.”
Egg Development (IVF Study)
In an IVF study by Piervito D'Elia et al. (2014):
- The MTHFR C677T polymorphism was associated with premature oocyte retrieval
- The A1298C variant was associated with fewer retrieved oocytes
Ovarian Stimulation & AMH
- The C677T variant is associated with higher baseline FSH and requires greater FSH stimulation during infertility treatment, suggesting lower ovarian sensitivity.
- Women with C677T produce fewer follicles and have lower AMH levels after ovarian stimulation, although they may have higher baseline AMH levels.
- Women with C677T also required more hCG to stimulate oocyte release. (Rosen et al., 2006)
- The C677T variant has been associated with premature ovarian insufficiency, while A1298C is associated with lower chances of successful pregnancy after IVF.
Endometrial Development & Implantation
MTHFR polymorphisms are associated with difficulty conceiving and early pregnancy loss due to endometrial and implantation problems (Ikeda, 2012). Not only progesterone, but also methylation is important for endometrial development and for the successful establishment of pregnancy.
Choi et al. (2016) — Recurrent Implantation Failure
“The combined MTHFR 677 / MTHFR 1298 genotype may be associated with an increased risk of recurrent implantation failure.” IVF studies consistently show that women with MTHFR mutations are more likely to experience recurrent implantation failure.
Methylation is essential for coordinating cell division and development — which is critically important for fertility, conception, and embryonic development. Folate provides the foundation for several building blocks of DNA, so folate deficiency may affect cell division and contribute to congenital defects.
Male Fertility & Sperm
The MTHFR C677T variant is clearly associated with male infertility, whereas the role of A1298C is less established.
Liu et al. (2015) — Meta-analysis of 37 Studies
“Our meta-analysis showed that the MTHFR C677T mutation is a risk factor for male infertilityboth in patients with azoospermia and in patients with oligoasthenoteratozoospermia, especially in the Asian population. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility. Genetic mutations in folate-related enzyme genes play a significant role in male infertility.”
When evaluating folate-cycle gene variants, we typically assess four points — MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G — not MTHFR alone. This is usually called: Genetic polymorphisms of the folate cycle — 4 points.
Sperm Count
Wong et al. (2002) — Double-Blind, Placebo-Controlled Trial
“The total number of normal sperm increased after combined treatment with zinc sulfate and folic acidin both subfertile and fertile men.” Zinc and folate improve fertility in both healthy men and men with reduced fertility.
Some men with fertility problems have low MTHFR function in sperm. Folate has been shown to improve sperm count and treatment success in infertility.
Homocysteine as a Fertility Marker
Blood homocysteine is an indicator of methylation status, although methylation problems may still occur even when homocysteine is within the normal range.
Elevated homocysteine is correlated with
- Lower estradiol and luteal-phase progesterone
- A 33% higher risk of anovulation, in both women with PCOS and those without
Low folate is not the only factor that can raise homocysteine — kidney and thyroid problems may also do so. Elevated homocysteine may also involve deficiencies of B2, B6, B9, B12, zinc, and TMG (betaine).
Interventions for MTHFR Polymorphisms
The most obvious intervention for MTHFR gene variants is supplementation with methylfolate (5-MTHF). However, the entire B-vitamin group functions in an interdependent relationship.
B12 Masking Risk
If there is a vitamin B12 deficiency and large doses of folate are added, the B12 deficiency may be masked — and that is dangerous. Where a B9 deficiency has developed, a single folate product should be layered on top of at least a B-complex, and ideally on top of a full vitamin/mineral complex.
When homocysteine is elevated, it is practical to work with formulas that include B12, B2, B6, B9, and TMG (betaine).
Folic Acid vs. Methylfolate
Long-term use of high-dose folic acid (>5 mg for >6 months) may eventually inhibit MTHFR function. Unmetabolized folic acid in the blood has also been associated with certain cancers. With MTHFR polymorphisms, the ability to metabolize folic acid is reduced even further. Because these adverse effects are not observed with methylfolate, methylfolate appears to be the safer and better choice, especially during pregnancy. (Ferrazzi et al., 2021) People with MTHFR mutations also need to pay attention to foods fortified with synthetic folic acid.
Medications That Can Cause Folate Deficiency
- Methotrexate
- Barbiturates
- Aspirin and salicylates
- Metformin (also causes B12 deficiency)
- Acid-reducing medications
- Hormonal contraceptives and estrogens
Lab Markers to Watch
The following laboratory findings may suggest deficiencies of B12, folate, B6, or methylation problems related to folate-cycle gene mutations:
- Blood vitamin B12 not in the optimal range or reduced
- Blood vitamin B9 below the optimal range
- Homocysteine elevated or above 7–8 (with low methionine)
- Elevated methylmalonic acid in urinary organic acids (B12)
- Elevated formiminoglutamic acid in urinary organic acids (B9)
- Elevated xanthurenic acid in urinary organic acids (B6)
- Elevated kynurenic acid (B6)
- Elevated leucine, isoleucine, and valine in blood
- Low HVA and low VMA on urinary catecholamine or organic acid testing
- High pyroglutamate
- Elevated anti-gliadin antibodies (celiac disease / gluten intolerance)
- Urinary estrogen metabolites and their ratios (methylation is critical for estrogen detoxification)
- Or a broader DUTCH test
The Bottom Line
If ovarian reserve is reduced and FSH is elevated, it is especially important to pay attention to MTHFR genotypes. Because MTHFR polymorphisms interact closely with epigenetics, lifestyle, environment, and other gene polymorphisms, they manifest differently in each individual.
Successful conception and pregnancy require attention to a number of polymorphisms — at minimum those of the folate cycle — as well as lifestyle correction. Testing for genetic polymorphisms and nutrient deficiencies should be done at the conception-planning stage, not after pregnancy loss. We need to learn to be proactive.
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