The Part MTHFR Plays in Infertility and Miscarriages

Infertility and miscarriage are devastating for both men and women. There is a wide range of reasons that infertility and miscarriages occur, but they often remain unexplained. 

Previously, research has suggested that at least half of miscarriages may be due to genetic abnormalities in the embryo, particularly chromosomal abnormalities. 

However, scientists have now detected that male and female infertility factors may include hormones, diet, and parental genetics. In particular, the MTHFR gene has emerged as a possible influence on male infertility and an increased risk of miscarriage. 

Understanding the MTHFR gene and how it affects your fertility is essential for anyone trying to have children. It’s especially important for women as it may affect their ability to get pregnant, the pregnancy itself, or the future child’s health.

This article will give an overview of the links between MTHFR, infertility, and miscarriage as well as whether having an MTHFR mutation can affect your chances of starting a family or not. We will also discuss possible health issues that can arise during pregnancy and the perinatal period and your options for minimizing these issues.

Folate is crucial for the healthy growth and development of the fetus, particularly in proper DNA replication. Demands for folate increase during pregnancy.

For this reason, women who are considering starting a family are generally recommended to take folic acid. 

However, a mutation on the MTHFR gene can impair the body’s ability to carry out the methylation process, which is crucial for converting folic acid into folate. This process is also required for the breakdown of homocysteine to methionine. 

Deficiencies of folate and high levels of homocysteine can lead to health issues for both fertility and pregnancy, including Neural Tube Defects (NTD) and pregnancy loss. 

Maternal homocysteine has an independent effect on placenta-mediated pregnancy complications. Elevated maternal homocysteine has been implicated in complications including preeclampsia, placental abruption, intrauterine growth restriction (IUGR), and miscarriage. These complications are all linked to abnormal placental vasculature. High levels of homocysteine have also been linked to poor fertility due to low ovulation. This appears to occur in women both with and without polycystic ovarian syndrome. 

Methylation is involved in the growth and development of important tissues required for a healthy pregnancy, including the endometrium. It’s also involved in proper ovulation. 

Healthy endometrium is essential for the successful implantation of the fertilized egg, so impairment of the methylation process may also affect the early stages of pregnancy.

Several studies have indicated that the MTHFR genetic mutations may be associated with male infertility. 

A meta-analysis of 37 studies showed that the MTHFR C677T mutation was a risk factor for both azoospermia (when there are no sperm in the ejaculate) and for oligoasthenoteratozoospermia (low sperm count). 

These conditions are especially noted in Asian men and can contribute significantly to poor male fertility. It was also found that men who were homozygous for 677TT were affected to a greater extent than heterozygous patients (C677T).

The MTHFR A1298C mutation appeared not to be related to male infertility.

MTHFR mutations affect the vital functions of folate-related enzymes. Homocysteine disrupts the synthesis of methionine, which in turn impacts negatively on protein synthesis and methylation. DNA repair can also be affected. A significant link between the incidence of methylation errors, defective sperm development, and the impact on embryonic development has now been well established.

Early pregnancy loss (EPL)

EPL rate is shown to increase with the degree of MTHFR polymorphism complexity. Pregnancy loss also appears to be significantly higher in patients with the C677T polymorphism compared to A1298C.

Neural tube defects

Neural tube defects include any congenital disability of the brain, spine, and/or spinal cord. They can result in nerve damage, learning disabilities, paralysis, and death.
The C677T gene is particularly associated with an increased risk of NTD.

Repeated miscarriage

The 1298AC and C677T/1298AC genotypes appear to be risk factors for unexplained repeated pregnancy loss. Pregnancy loss also appears to be highest in women with two mutations (homozygous) of either A1298C or C677T.

Intrauterine growth retardation (IUGR)

IUGR occurs when the fetus does not grow as expected. The C677T polymorphism is associated with an increased risk of IUGR and placental abruption in the global population, especially in Caucasians and Africans.

Preeclampsia (high blood pressure during pregnancy)

The C677T genotype is associated with increased risk for PE, especially in Asians and Caucasians.

Ablation placenta (partial or complete separation of the placenta from the inner wall of the uterus before delivery)

While some studies have linked C677T with increased risk for placenta ablation, others have not.

Fetal aneuploidies (presence or absence of one or more chromosomes)

MTHFR is shown to be one of the few known human genes that can modulate rates of chromosome abnormality, in which either the number or structure of chromosomes are altered. For this reason, there is a correlation of C677T with Down syndrome and neural tube defects in the fetus.

Preterm delivery (babies born alive before 37 weeks of pregnancy)

The C677T polymorphism may increase the risk of premature delivery, while the A1298C may reduce the risk. 

Congenital abnormalities

A wide range of structural or functional abnormalities of prenatal origin with significant medical, social or cosmetic consequences, usually requiring medical intervention (e.g., cleft lip, spina bifida). 

The C677T type is a risk factor for congenital heart defects.

Stillbirth/pregnancy loss

A meta-analysis of the A1298C polymorphism in both repeat pregnancy loss and in miscarriage suggested that A1298C can increase the risk for pregnancy loss.

Many of the adverse pregnancy and perinatal outcomes associated with MTHFR stem from the body’s inability to process and use folate. 

Homocysteine-methionine and MTHFR-related biochemical pathways are required for an enormous range of biological processes during pregnancy, including the synthesis of various nucleotides and DNA methylation.

Those with the MTHFR polymorphism - especially C677T - have very low activity of the MTHFR enzyme. This reduces their ability to convert folic acid into a usable form and can lead to the accumulation of the toxic amino acid homocysteine.

Those with MTHFR are advised to avoid foods and supplements containing synthetic folic acid. This includes fortified foods. 

Instead, they should choose foods that contain natural forms of folate. Folate-rich foods include:

• Dark, leafy greens
• Fresh fruits and raw juices
• Nuts
• Beans
• Peas
• Seafood
• Eggs
• Dairy products
• Meat
• Poultry
• Grains

Other foods that support healthy methylation include asparagus, avocado, broccoli, and legumes.

Taking the bioavailable form of folate is the most effective way to provide adequate amounts of this nutrient. One study compared women who used a prenatal supplement that contained L-methylfolate with women who took folic acid. The L-methylfolate supplement resulted in significantly higher hemoglobin levels at the end of the second trimester and at delivery, including a lower incidence of anemia and adverse outcomes. 

Supplementation with folic acid has also been linked to adverse health issues, including masking vitamin B12 deficiency. In offspring, folic acid may increase the risk of insulin resistance, certain cancers, depression, cognitive impairment, as well as reduced size. 

Unlike folic acid, methylfolate is already converted to its usable form. It can bypass an MTHFR polymorphism and cross the blood-brain barrier for immediate use in the body. 

Supplementing methylfolate is crucial, both before and after conception, especially for women with the C677T mutation. C677T has been associated with an increased risk of NTD in numerous studies; however, methylfolate has been shown to increase plasma folate more effectively than folic acid in women with the homozygous or wild-type C667T.

The Methyl-Life® product range including our Methylated Multivitamin, B-Methylated II, and Methylfolate 2.5 supplements are well suited to those with an MTHFR mutation who are considering starting a family. 

These best-selling products are formulated with Magnafolate® PRO, a proprietary form of methylfolate shown to be more pure and stable than the other L-Methylfolates available on the health supplement market today.