You’re taking your Folic Acid supplements regularly so you don’t need to worry about getting Folate from your diet.  Right?   Well… the availability of the right form of Folate may affect hormone balance, implantation, mood, miscarriage, pre-eclampsia and pre-term birth risk in some people.

Here’s what you need to know.

1.     We need Methylfolate - which is the active form our body can use

• Folic Acid is the synthetic form which is in most supplements

• Folate is the natural form found in food

• Both Folic Acid and Folate are converted to Methylfolate in the body

• Some people have less of the active enzyme needed for the conversion – this is because of a genetic variation called the MTHFR variant (scroll down for the technical bit)

• We can get Methylfolate from food

2.     Methylfolate levels may affect fertility

PCOS – A methylfolate supplement combination showed more improvement in menstrual cycle regularity, BMI reduction, testosterone and homocysteine reduction and insulin sensitivity.  The recent Italian study compared treatment with combined myo-inositol, gymnemic acid and methylfolate to treatment with myo-inositol plus folic acid in women with PCOS.

The MTHFR variant - Approximately 10% of the UK have a genetic variation called homozygous C677T which means they can’t make methylfolate so efficiently.  This has been associated with recurrent implantation failure, low mood, higher homocysteine which may affect DNA quality, higher miscarriage risk and pre-eclampsia.

• Recurrent implantation failure rates were higher in women with the variant in a Korean review study

• High homocysteine - Last year a French study found that infertile couples with the variant had higher homocysteine levels - but this reduced with 600mcg methylfolate supplements daily – the study suggests that people with the variant should be treated with methylfolate instead of high dose folic acid

  • In May the same researchers published a case history of a woman who’s homocysteine increased to 17.2 micromol/L on high dose folic acid 5mg, and decreased to 8.2 micromol/L when switched to 500mcg methylfolate.

Methylfolate may also affect mood while trying to conceive and during pregnancy - In February a study found that a prenatal supplement containing methyfolate offered some protective effect against depression in women who had a previous diagnosis of depression.

3.     Methylfolate levels may affect pregnancy and miscarriage risk

Miscarriage – 16 women with MTHFR variations and a history of 3 or more miscarriages were given high dose Methylfolate 5mg daily plus B6 50mg daily and B12 1mg weekly resulting in reduced homocysteine levels and 7 live births

Pre-term birth - Recent reviews have found an association between the C677T variant and preterm birth and low birth weight (Wu et al. 2017) (Fang et al. 2018) though not all previous studies demonstrate this.

4.     Food contains both folate and methylfolate

‘eating the rainbow’ helps methylfolate levels - rich sources include

• green leafy vegetables, spinach, kale, cabbage, broccoli, cauliflower, asparagus, lettuce, peas - vegetables are best lightly cooked or raw

• strawberries, blueberries and other berries - including frozen

• oranges, grapefruits and citrus fruits - including juices

beans and pulses are rich sources of folate but this is not in the methylfolate form unless they are sprouted

5.     Folic acid is important! - and expert opinions vary on the best form of folate

Folic acid is the most cost effective and available way of reducing birth defects. It protects against neural tube defects and supplementing is an important part of prenatal care.  For most people it is the cheapest way of providing essential folate supplementation during pre-conception and pregnancy. 

The UK government is currently consulting on fortifying bread and flour with folic acid to help prevent neural tube defects and confer other health benefits.  A 2015 study estimates that 2000 fewer neural tube defect pregnancies would have occurred since 1998 if the UK had adopted the same policy as the USA in fortifying flour with folic acid.

• Red blood cell folate was below the protective level for birth defects in 91% of women of childbearing age in a National Diet and Nutrition Survey

• Start taking extra folate before trying to conceive - 3 months is ideal

Not everyone agrees that methylfolate may be a better treatment

• Professor Anne Molloy states that maintaining good levels of folate with Folic Acid supplements helps people with the MTFHR variant and that MTHFR testing is not necessary

• A study published in May found that when infertile men with the MTHFR variant took 800mcg of folic acid for 3 months their sperm quality, DNA fragmentation and pregnancy outcome improved

6.     You need vitamins B12 B6 and B2 to help your body use folate

Taking folate as part of a prenatal that contains other B vitamins is better than taking it on its own.  The other B vitamins help you utilise folate and help keep homocysteine low

• B12 is needed to help methylfolate work

• B12 deficiency and high homocysteine have been associated with miscarriage in women with the C677T variant

• High homocysteine can be caused by deficiency in folate, B12 and B6 as well as by the MTHFR variant

• taking a supplement with at least 2.5mcg vitamin B12 daily is recommended with your folate

7.     The MTHFR variant – how to get tested

If you have a history of recurrent miscarriage or a diagnosis of unexplained infertility it may be worth getting tested, though maintaining a good intake of folate and other B vitamins through both diet and supplements is the first essential.

• Your GP can do blood tests for folate levels and homocysteine levels – if they are normal then even if you have the variant it isn’t affecting you adversely

• Saliva tests are available online to check for the MTHFR variant. Prices start at £80.

  • The test will tell you if you have any MTHFR variants – only the homozygous C677T variant has been shown to have implications for fertility, the heterozygous form is common and shouldn’t be a cause for concern.

summary - key points for helping fertility with folate

• Preparation is key – start changing your diet and taking a preconception supplement before trying to conceive

• Folic Acid as part of a prenatal will be adequate as a supplement for most women

• Eating leafy green vegetables, berries and citrus fruit daily will supply Methylfolate

• If you have had recurrent miscarriages or IVF failures consider switching to a prenatal containing L-Methylfolate

• Don’t take folic acid on it’s own - choose a preconception or prenatal multivitamin with at least 2.5mcg B12

• Men need folate for their fertility too

The technical bit

The terminology can get confusing…

• MTHF is methylfolate (L-5-methyltetrahydrofolate) also known as L-methylfolate

• MTHFR is the enzyme needed to produce methylfolate

• MTHFR variant is the genetic variation

• Homocysteine is an amino acid

how genetics affect the MTHFR enzyme

The enzyme needed to convert folic acid or folate into a usable form is called 5-MTHF reductase (MTHFR) – it allows recycling of the amino acid homocysteine to methionine.

• If MTHFR levels are low then homocysteine levels can build up and this has been linked to infertility, miscarriage, birth defects, mental health problems and heart disease

• High homocysteine causes oxidative stress and can affect DNA

Some people have a genetic variation called the MTHFR variant

• There are about 30 types of variant

• Each variant may be heterozygous or homozygous

  • Homozygous means that both of the gene pair are affected by the variant - so it’s effects are more severe

• A variant called C677T is the one that has been studied most

• Homozygous C677T is linked to lower folate and higher homocysteine levels

• Appoximately 10% of the UK population has the homozygous C677T variant and the incidence is higher in people of Mediterranean decent