How Does Birth Control Interact with an MTHFR Gene Mutation?

Birth control is a popular and effective form of contraception, used by around 14% of US women aged 15-49. Besides preventing pregnancy, hormonal birth control may be taken for a range of reasons, including regulating menstruation and balancing hormones. 

However, as with any medication, the contraceptive pill carries a few contraindications, including blood clots, migraine headaches, high blood pressure, and high cholesterol. 

It has also been found that oral contraceptive use in women of childbearing age can lead to compromised folate status. This may be problematic for women with an MTHFR gene mutation, particularly as folate is crucial in fetal development. A significant proportion of the population (more than 25% of Hispanics and 10-15% of North America Caucasians) are estimated to be homozygous for the TT genotype MTHFR 677C > T.

This article will discuss whether oral contraceptives may increase health risks for someone with an MTHFR gene mutation and whether MTHFR hinders contraceptives’ effectiveness. We will also discuss potential alternatives to oral contraceptives or whether supplementation may help reduce risks. 

MTHFR is the critical enzyme for almost all biological processes that involve folate and methionine metabolism. However, those with an MTHFR genetic mutation have a defective MTHFR enzyme and cannot process folate effectively. 

Low folate levels are a common symptom of MTHFR mutations, along with higher levels of non-methylated forms of folate. Lower levels of vitamin B12 are also common in MTHFR mutations, particularly the C677T polymorphism. 

A systematic review involving a total of 2,831 women in 17 studies showed that oral contraceptive use in women of childbearing age might significantly reduce folate levels. 

B12 and folate are both required for converting homocysteine to methionine, red blood cell production, and nervous system maintenance. Deficiency of either nutrient may lead to elevated homocysteine levels, a significant risk factor for cardiovascular disease and many other chronic conditions such as diabetes. This is a common risk factor for those with MTHFR mutations.

Those with the MTHFR 677 TT genotype (this is considered a double mutation) have about 25% higher homocysteine levels than those with the 677 CC genotype (no mutation), but the impact of the MTHFR polymorphism varies according to folate status.

The use of oral contraceptives by those with the MTHFR mutation may also increase the risk for venous thromboembolism. One study highlighted that the presence of more than one of the prothrombotic polymorphisms, including MTHFR, was associated with a substantial risk of thromboembolism.

A 2005 study also showed that women with the C677T genotype were 50% more likely to have had arterial thrombosis. The same study noted that women with the C677T genotype who used oral contraceptives had a risk of ischemic stroke five times higher than women who had neither the factor V Leiden variant (a mutation of one of the blood clotting factors) nor an MTHFR genotype. 

Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Deficiency of B12 is a major cause of fatigue, neurological disorders, anxiety, nerve pain, and depression, along with pernicious anemia and megaloblastic anemia.  

For these reasons, women with an MTHFR mutation taking oral contraceptives may be at an even higher risk of health concerns associated with folate and B12 deficiency. 

When used correctly, the effectiveness of oral contraceptives is around 99%. However, missing a dose reduces the efficacy. 

Some medications can interfere with the effectiveness of contraceptives, including anti-seizure medications, the herb St John’s Wort, and the antibiotic Rifampin (other antibiotics do not affect the pill). 

However, there appear to be no reports of the MTHFR gene mutation affecting oral contraceptive effectiveness.

Women with a family history of thrombophilia, such as factor V Leiden (a mutation in one of the blood clotting factors), are advised to undergo screening for thrombophilic defects before taking the contraceptive pill. 

Women who have the C677T polymorphism are also at a higher risk of thromboembolism. For these reasons, alternatives to the oral contraceptive pill may be recommended. Options include:

The impact on folate caused by oral contraceptives means it is highly advisable for women to take folate supplements while taking the pill. This is even more important for women with the MTHFR mutation and those who stop taking the pill to start a family. 

A 2009 study showed that around 45.7% of women who stop using the pill become pregnant within three months. These women may be at a higher risk of neural tube complications due to low folate status during the preconception period, especially if they have an MTHFR mutation(s) and are already at risk of being deficient in folate. 

Folate supplementation has been shown to reduce the risk of neural tube defects that occur in the first four weeks after conception. However, many women are unaware they are pregnant at this stage.

During pregnancy, adequate supplementation with folate is crucial for proper methylation, which contributes to the healthy growth and development of the fetus. Folate deficiency and impaired methylation have been linked to pregnancy complications, including miscarriage, neural tube defects, preeclampsia, poor neonatal brain development, anemia, and peripheral neuropathy.

Supplementation with methylfolate has been shown to effectively improve folate biomarkers in young women in early pregnancy, which can prevent neural tube defects. 

Pregnant women with an MTHFR mutation are advised to avoid folic acid and instead supplement with active 5-methyl-THF (methylfolate). Studies show that methylfolate bypasses the MTHFR block, making it an effective treatment for women with MTHFR. Methylfolate is also shown to be more effective than folic acid in improving folate status and is recommended as an efficient and safe alternative.

Some of the most stable and biologically active folate supplements are those that include ((6S)-5-methyltetrahydrofolate or (6S)-5-MTHF), ((6S)-5-methyl-tetrahydrofolic acid, calcium salt, or L-methylfolate) and ((6S)-5-methyltetrahydrofolic acid, monosodium salt, or L-methylfolate). 

These forms of methylfolate are used in Methyl-Life® products as Magnafolate® PRO. Studies have shown that Magnafolate® PRO offers superior particle size distribution, stability, dissolution, potency, bioavailability, and safety.