Written by Dr Phoebe Howells. Reviewed by Dr Katherine Joseph. Last reviewed and updated on 29.0926. 

Phoebe, a doctor since 2012, has a decade of experience in Obstetrics and Gynaecology, with a focus on fertility. Her dedication led to a clinical fellowship in Reproductive Medicine at London Women’s Clinic. She's authored articles, shared insights at global conferences, and contributed to fertility trials for women with adenomyosis. Phoebe's all about crafting tailored, evidence-based care and achieving the best results for people navigating fertility challenges. While working in London, she enjoys the countryside life in Kent.

Folate, Folic Acid and MTHFR: why the form you take matters

Folic Acid is the one we’ve all heard of. Recommended by the NHS when trying to conceive and for the first trimester of pregnancy, 400 micrograms is the daily amount advised to help prevent birth defects known as neural tube defects, including spina bifida.

However, as research into fertility and micronutrition has evolved, so too has our understanding of folate, including how different forms are absorbed and used by the body. At OVUM, alongside many others in the field, we continue to advocate for updated guidance that reflects this growing body of evidence.

Folate

Let’s start with folate itself. This is the umbrella term for a group of compounds that make up vitamin B9. From there, folate can exist in different forms, most commonly:

• Folic Acid (synthetic form) 

• Methylfolate (the naturally occurring, active form) 

Why folate matters for fertility

Folate plays a central role at every stage of fertility, from egg development and ovulation through to early foetal growth. It is widely recommended during the first 12 weeks of pregnancy, but its importance begins well before conception.

Emerging research suggests that folate may:

• Support ovulation 

• Improve egg quality 

• Contribute to embryo development 

• Influence overall pregnancy outcomes 

Higher folate intake has been associated with:

• Reduced risk of infertility 

• Shorter time to conception 

• Lower risk of pregnancy loss 

• Improved outcomes in fertility treatments 

Folate also appears to play a role in egg maturation, with higher follicular folate levels associated with improved pregnancy rates in people undergoing fertility treatment. 

Folate and fertility treatment outcomes

Research in assisted reproductive technologies (ART), including IVF, IUI and ICSI, continues to highlight the importance of folate status.

A Harvard study found that women taking 800 micrograms of folate per day during fertility treatment had a higher probability of live birth. Other studies have reported higher fertilisation rates and lower cycle failure rates before embryo transfer.

Recent research continues to strengthen the link between folate status and fertility outcomes. Studies in IVF populations consistently show that higher folate levels are associated with improved embryo quality and pregnancy rates.

At the same time, emerging clinical trials comparing methylfolate to folic acid suggest that methylfolate may improve folate biomarkers and reduce circulating levels of unmetabolised folic acid. However, large-scale studies comparing pregnancy and birth outcomes between the two forms are still lacking, meaning both remain relevant depending on the stage of the fertility journey.

So, what are the different forms of folate?

Folic Acid

Folic acid is a synthetic form of folate used in most prenatal and fertility supplements. Before the body can use it, it must first be converted into its active form.

The efficiency of this conversion varies between individuals. Genetic variations, including those affecting folate metabolism, can reduce the effectiveness of folic acid processing in some people.

Another consideration is that high folic acid intake may mask symptoms of vitamin B12 deficiency if not monitored appropriately.

Methylfolate

Methylfolate is the naturally occurring, bioactive form of folate found in the body. Because it is already in its active form, it can be used immediately without requiring conversion.

Research shows that methylfolate can be more effective at raising blood folate levels than folic acid and may be particularly beneficial for individuals with variations in folate metabolism (e.g. the MTHFR gene).

Why does the form matter?

While both forms contribute to overall folate status, how efficiently they are used by the body can differ.

Some individuals have genetic variations that affect folate metabolism, which may reduce their ability to convert folic acid into its active form. This can impact the availability of folate for key processes in the body.

One of folate’s important roles is helping regulate homocysteine levels, a byproduct of normal metabolism. Elevated homocysteine has been associated with poorer fertility outcomes and reduced embryo quality in IVF populations.

Ensuring adequate levels of bioavailable folate may help support these pathways more effectively.

What if I’ve been prescribed high-dose folic acid?

In some cases, a GP or fertility specialist may prescribe a higher dose of folic acid (typically 5mg). This is often recommended in specific clinical situations where folate requirements are increased, or folate metabolism may be impaired. This includes women who have had a previous pregnancy affected by a neural tube defect (such as spina bifida), those with pre-existing diabetes (type 1 or type 2), and individuals with a higher BMI (typically ≥30), all of whom have an increased baseline risk of neural tube defects. It is also recommended for those taking certain medications that interfere with folate metabolism or absorption, such as some anti-epileptic drugs, as well as in people with malabsorption conditions like coeliac disease, inflammatory bowel disease, or a history of bariatric surgery. In addition, it may be advised for individuals with haemoglobin disorders such as sickle cell disease or thalassaemia due to increased folate turnover, and in some fertility or recurrent pregnancy loss contexts where clinicians identify potential additional risk factors.

If you've been prescribed 5mg folic acid, that prescription takes priority, and we'd always recommend following your healthcare provider's guidance. You can still take Time to Conceive® For Women alongside your prescription, as the additional methylfolate is not considered harmful. However, the extra folate is not necessary in this context, and we recommend informing your healthcare provider before combining supplements. It’s also important to ensure your Vitamin B12 levels are monitored, as high doses of folic acid can mask a deficiency.

What happens once you’re pregnant?

While methylfolate is often prioritised during preconception, guidance shifts slightly once pregnancy is confirmed.

The NHS recommends 400 micrograms of folic acid daily until week 12 of pregnancy, based on strong evidence showing it reduces the risk of neural tube defects.

This recommendation is grounded in large-scale studies that specifically used folic acid. To date, there have been no equivalent large-scale trials directly comparing methylfolate and folic acid for neural tube defect prevention. Realistically, given that Folic Acid is effective in the vast majority of cases, there will never be funding or ethical approval for a comparison study for Methylfolate vs Folic Acid.

Because of this, many experts support a combined approach during early pregnancy using folic acid to align with established guidelines, and the correct form to use until week 12 of a pregnancy when the neural tube closes, while also including methylfolate to support broader folate metabolism, and for its wider benefits in the pregnancy beyond the 12-week mark.

Key Takeaways

• When it comes to folate supplementation, both form and dosage matter. Because absorption and conversion of folic acid can vary, many experts now recommend focusing on bioavailable forms of folate, particularly when trying to conceive. 

• At the same time, established clinical guidance still supports the use of folic acid in early pregnancy for neural tube defect prevention. 

• Taking a stage-specific approach, considering both individual needs and the latest evidence, is key.