Introduction

If you are a woman, there’s a decent chance you have heard about folic acid, and its importance in helping a baby grow and develop well. As a next step, you may have even started looking into your daily women’s multivitamin or your prenatal vitamin ingredients (if you’re planning to be pregnant or are pregnant) to see if it contains folic acid. You may have taken this whole research thing a step further, because you’re a nerd (like us), and researched folic acid in your prenatal vitamin and discovered that some newer brands contain another type of folate called 5-methyltetrahydrofolate (5-MTHF) instead. So what if your multivitamin contained 5-MTHF? What does that mean? If you haven’t even heard of any of this content, don’t fear! We are going to go through it in depth here.

There’s lots and lots of prenatal vitamins out there, and they contain an array of different ingredients and dosages (see our blog on prenatal vitamin essentials). Some contain folic acid and some contain a different form of folate. But what is the difference? What is recommended? 

The forms

To understand folic acid versus folate, let’s first dive into the different forms, what they do, and some of the complex processes they are a part of. 

Folates:

Just know that there are around “150 folate compounds,” but we will discuss a few here.⁸ 

• Tetrahydrofolate (THF)→ naturally found in foods (i.e., beef liver, spinach, black-eyed peas, asparagus, brussels sprouts, avocado, broccoli)⁴ 

• Folinic acid → known as 5-formyltetrahydrofolate or 5-formylTHF. Converts to 5-MTHF without DHFR (see figure below).
• 5-methyltetrahydrofolate (5-MTHF) → can be found naturally, forms that are man-made in supplements are synthetic 
• Folic acid → is a synthetic form. It is obtained by ingesting fortified foods (i.e. cereals, flours, breads, supplements, etc.) and has a high bioavailability.⁷

 A note on folate in the body: 

• Circulating folate in the blood – plasma folate, is in the form of 5-MTHF
• Folate stored in Red Blood Cells (RBCs) or erythrocyte folate is a good indication of the body’s true storage of folate and the amount of it, because an RBC has a lifespan of 120 days.⁷

To calculate the dosing of folic acid or folate from a Dietary Folate Equivalent (DFE) there are certain conversions as stated here:

• Conversions
  • Folic acid
    • 1 mcg DFE = 1 mcg dietary folate
    • 1 mcg DFE = 0.6 mcg folic acid (taken with food)¹⁷
    • 1 mcg DFE = 0.5 mcg folic acid (taken on an empty stomach)¹⁷
    • 1.7 mcg DFE = 1 mcg folic acid
  • Folate
    • 1.7 mcg DFE = 1 mcg 5-MTHF³
• The RDA, ACOG, and other organizations recommend 600 mcg DFE.
  • Using the above formula, that would mean:
    • 600 mcg DFE = 353 mcg folic acid

The biochemistry

This is going to get complex, but hang in there. If this is too much science info, no worries, feel free to skip to the next section. However, this can help you understand why folate and folic acid help key bodily processes. I encourage you to refer to the diagram below as you read through this section. Visuals are key to understanding biochemistry!

Okay, let’s look at this process when it comes to folate in food. Some foods contain folate that comes in the form of a polyglutamate. Folate contains glutamate groups (either one or multiple), making them polyglutamates (multiple glutamate residues, specifically 8) or just one (monoglutamate).⁸ This is important when it comes to how folates move throughout the body. The process of polyglutamylation, or adding glutamates to a form of folate can make the molecule less stable and it is not as easily absorbed. Just one glutamic acid group on a folate molecule, a monoglutamate, can be more transferable across a cell membrane and are more stable.⁸

Polyglutamate folate must be broken down into a monoglutamate in order to pass through the cells of our intestine and into our blood for use. Folic acid is in a monoglutamate form when absorbed in a supplement or fortified food. Another folate form, 5-methyltetrahydrofolate (5-MTHF) is also in a monoglutamate form.⁴ There are multiple synthetic or man-made versions of this more active form (i.e. Quatrefolic). These forms can diffuse easily through the mucosa. 

Once the monoglutamate folate molecules have travelled through the mucosa and into our tissue cells from the bloodstream, they are re-converted to a polyglutamate to enter the methylation cycle.⁷ Dihydrofolate (DHF) enters what is called the methylation cycle (see below), and is converted to THF. THF is converted to 5,10-methyleneTHF. MTHFR helps synthesize 5,10-methyleneTHF to 5-MTHF. Vitamin B12 (and zinc, choline, B6, and B2¹⁷) is used during this conversion process.⁷ How are these different types of folate used?

1. SAM methylation pathway: 5-MTHF, along with B12, is used to convert homocysteine (Hcy) to Methionine, which is a part of the process to create S-Adenosylmethionine (SAM). SAM is a major methyl donor. Methyl donor? Methyl groups that are donated to other molecules help turn off genes and their expression of proteins. They are a key part of our body’s regulation.⁴ Folate deficiency can lead to increased homocysteine and decreased SAM.⁸
   1. If there is a deficiency in 5-MTHF, then Homocysteine levels will increase. A deficiency in 5-MTHF could be due to decreased MTHFR activity.
   2. If there is a vitamin B12 deficiency (or zinc deficiency), then this can contribute to decreased methionine, increased homocysteine, and low THF. This can lead to infertility.¹⁴ 
2. Thymidylate cycle: Helps synthesize dTMP or thymine, which is a key nucleotide necessary for the creation of DNA. Specifically, tetrahydrofolate (THF) is converted to 5,10-methyleneTHF. 5,10-methyltheneTHF donates a methyl group (a part of the molecule, specifically CH3 group) to dUMP (another molecule) that helps create thymine, which is the “T” in the ACTG (4 main building blocks or bases of DNA if you go back to 9th grade science class).⁵ Vitamin B12 also helps in this synthesis process.⁷

3. Purine synthesis: Like the thymidylate cycle, THF is used to create nucleic acid for DNA synthesis. THF is converted to 10-formyl-THF which helps form AMP and GMP. These are the “A” and “G” in the ACTG (4 main building blocks or bases of DNA).
4. Transsulfuration pathway: Homocysteine forms cystathionine. A sulfur group from cystathionine is cleaved, which forms cysteine. Cysteine is synthesized to glutathione, which is an antioxidant that can help decrease oxidative stress, helps with the immune system, and detoxification of pollutants (you may have heard of this in a supplement before).⁶ If there is an impairment in methylation, and part of this cycle, it can lead to inability to reduce oxidative stress.¹⁴

So overall, at the molecular level, folate plays a HUGE role in the creation of our DNA, RNA, and amino acids.⁴

If you want to read about these pathways more in depth, I highly recommend looking at this source. 

Questions around MTHFR gene variants and testing

We hear a lot about MTHFR gene variants. Some examples include C677T and A1298C. C677T is the most common. There are two chromosomes with the gene. Two copies of the variant would suggest a person is homozygous, one copy of the variant suggests a heterozygous gene. Homozygous gene variants can lead up to 70% deficiency of MTHFR activity, decreasing the amount of 5-MTHF. It is most common in Hispanics (25%) and caucasians (10%).⁴ 

• What if a person has an MTHFR gene variant? What does this mean?
  • Hypothetically, if a woman’s metabolism of folic acid to 5-MTHF was slower and less efficient due to an MTHFR gene variant, then she may have more unmetabolized folic acid (UMFA). The consequences of UMFA are unknown, and presents an issue that needs focus and study. Could there be none? Potentially. But it is an issue that the medical research community should dive into. See more on this below.
  • If there is decreased MTHFR activity, the result is often increased homocysteine and reduced SAM levels (see diagram above). But this can be remedied by increasing folic acid or 5-MTHF supplementation.⁸
    •  However, one study found that MTHFR gene variants with elevated homocysteine levels are most commonly found in men.¹⁴
  • Increased levels of homocysteine have been associated with poor maternal and fetal outcomes: preterm birth, miscarriages (especially recurrent), and intrauterine growth issues.⁸ Patients with recurrent miscarriages that have elevated homocysteine levels were shown to have a reduction in levels with 800 mcg of folic acid supplementation.⁸
  • Is genetic testing for an MTHFR gene variant necessary if I am trying to conceive (TTC)? ACOG does not recommend routine testing because there is no evidence that MTHFR gene variants directly relate to increased miscarriage rates.³⁴
  • Is homocysteine level testing necessary? It may show decreased 5-MTHF, but homocysteine levels can also be affected by many other factors as well. So drawing a single homocysteine lab value does not immediately equal a 5-MTHF deficiency or MTHFR issue.⁴ However, elevated homocysteine levels can correlate to an increased risk of NTDs.

Even for individuals with an MTHFR variant, the CDC recommends folic acid supplementation over 5-MTHF for prevention of neural tube defects.⁴

Other evidence: 

• One study was conducted with women with the C677TT homozygous genotype (meaning two copies of the gene variant). They found that women who were participating in egg retrieval for IVF had lower egg retrieval amounts. They also had reduced Anti-Mullarian hormone (AMH). AMH tests the amount of eggs a woman has in her ovarian reserve (number of eggs in the ovary). Specifically, women that had two copies of the C677T gene variant (C677TT) were found to have even lower AMH than women with a heterozygous variant (1 copy of the gene variant or C677T). Folic acid supplementation of at least 800 mcg helped compensate for these negative effects on the ovaries.⁸ 
• Another case-control study analyzed the genes of 395 individuals from 5 months to 52 years with spina bifida or encephalocele in Ireland, along with 848 controls. They found that heterozygosity of C677T polymorphism (one copy) may also increase the risk of neural tube defects. Previous studies have shown that homozygosity of C677T may moderately increase the risk of neural tube defects, but heterozygosity was also found to potentially increase this risk in this particular study.¹⁵ 

A note on UMFA, Autism Spectrum Disorder

Unmetabolized Folic Acid (UMFA) Evidence:  

• Detectable levels of UMFA in cord blood from a mother taking 400 mcg of folic acid were detectable but small, and were similar to that of mothers who did not take folic acid. Additionally, 400 mcg of folic acid taken in the second and third trimesters resulted in higher blood plasma folate and 5-MTHF. Only 8 out of the 53 cord blood samples had UMFA, and the levels of FA detected were similar in that of the folic acid group and the placebo group. This showed that UMFA in mothers who took 400 mcg of folic acid throughout their pregnancy had low or undetectable levels of UMFA in mothers or newborns.²⁹
  • Inclusion criteria: women who were 18-35 years old who had been taking 400 mcg of folic acid in the first trimester as recommended, and were randomly assigned 400 mcg of folic acid or none in the second trimester until delivery. 
• A study was conducted looking at UFMA levels in maternal and cord plasma of 368 Canadian women who were taking high levels of folate (median level of 1000 mcg folic acid). “UMFA was detectable in >90% of maternal and cord plasma samples.” This UMFA in fetal circulation may have adverse health effects.¹⁸
• In the National Health and Nutrition Examination Survey (NHANES) study that was completed from 2011-2016, a fasting individual’s serum folate levels were measured post-folic acid fortification.
  • UMFA was detected in 10.6% of users who took folic acid supplements and 2.22% of those who did not take a folic acid supplement. 
  • UMFA was highest in those who were >70 years old. 

A few narrative studies have concerns with UMFA due to its potential to compete with 5-MTHF for folate transporters and receptors. This could lead to increased homocysteine levels if there is reduced 5-MTHF.^13,14 

It is known that 5-MTHF (the active form of folate) can reduce the potential for UMFA, compared to folic acid.^25,26

Autism Spectrum Disorder Evidence: 

• A systemic review was completed in 2023 for the United States Preventative Services Task Force (USPSTF). “Nine new observational studies found no evidence of harms related to multiple gestation, autism, or maternal cancer.”²²
• The CHARGE (Childhood Autism Risks from Genetics and the Environment) study is a large study from 2003-2009 looking at environmental and other risk factors for autism and other developmental disorders. 429 children diagnosed with ASD and 278 neurotypical children were included between 24-60 months of age. They found that mean folic acid intake was “significantly greater for mothers of typical development children than for mothers of children with ASD in the first month of pregnancy.” Folic acid intake of >600 mcg during the first periconceptual period was associated with reduced ASD. Folic acid consumption and the risk of ASD was significant for mothers and children with C677T gene variants. Overall, they found that periconceptual folic acid intake (>600 mcg) was associated with reduced risk of ASD for mothers who cannot efficiently metabolize folate.³² 
• One study observed mothers who took 400 mcg folic acid at least 4 weeks prior to pregnancy and 8 weeks post-partum. They found that supplementation with folic acid can potentially reduce the risk of autism by 39% compared to mothers who did not take supplements.⁴
• Mothers exposed to indoor pesticides and were simultaneously taking 800 mcg folic acid had an increased risk of ASD.⁴
• Increased UMFA related to neurodevelopmental disorders:
  • Meta analysis study was conducted on maternal nutrition and risk of neurodevelopmental outcomes in their children. They found an inverse relationship between maternal folic acid/multivitamin supplementation and risk of a child developing ASD.³³
  • The Boston Birth Control (BBC) cohort study looked into UMFA in children from birth.²⁷
    • 567 children were recruited. 92 of the children were diagnosed with Autism Spectrum Disorder (ASD) and the other 475 children were neurotypical. 
    • Cord blood UMFA in the highest quartile was associated with increased risk of ASD, particularly in Black children. 
    • 5-MTHF and total folate were not associated with increased risk of ASD.
    • There is not a clear correlation between UMFA and ASD.
      • Some limitations to this study include: small cohort size, diagnosis of ASD classified by a physician not through as reliable ASD diagnosis criteria, and maternal UMFA was not measured. 
  • A Norwegian study found no correlation between cord blood UMFA and ASD in mothers who are treated with anti-seizure medication (which can reduce folate status).³⁰
  • A meta analysis completed in 2020 reviewed 15 manuscripts and found an association between C677T MTHFR gene variants and ASD risk, but no correlation between ASD and the A1298C gene variant.³¹
    • Limitations to this study included no differentiation between sex, environmental risk factors, and focused on Caucasians and Asians but not other ethnicities. 

Neural Tube Defect Evidence

What is a neural tube defect? 

• To first understand a defect of the neural tube, we need to define what a neural tube is. The neural tube is a part of a growing embryo that forms the basis of our nervous system (spinal cord, brain, nerves). This process is called neurulation. It begins 21 days after fertilization, and completes around 28 days post fertilization. Therefore, this process occurs within the first month or so after conception, a time when most do not even know they are pregnant. Completion is characterized by closure of the neural tube. Neural tube defects occur when there are issues with the closure.⁷ 
• Some types of neural tube defects include anencephaly and spina bifida.⁷

What causes them? There are multiple factors that can contribute to NTDs.

• Genetics: some studies show changes in mother’s ability to metabolize homocysteine. However, mouse studies that have attempted to reproduce NTDs by increasing homocysteine have not always been successful.⁷ There have been some mouse studies that have found other genes involved in methylation may contribute to NTD effects.¹⁴
• Higher rates of NTDs found in Hispanic women.¹⁷
• Lower socioeconomic status was correlated with increased incidence of NTDs.⁷
• Certain medications (account for <1% of causes of NTD): aminopterin, valproate, carbamazepine, isotretinoin (Accutane), clomiphene (agent to help with ovulation).⁷

In terms of how folate is involved in the reduction of NTDs, this mechanism is unknown. It is hypothesized that the folate can contribute to DNA synthesis during formation of the neural tube or assist with a metabolic pathway during fetal development.⁷

Studies: 

• A randomized controlled trial, known as the MRC Vitamin Study, was conducted in 1991. 1817 women were analyzed, who were suspected to have a high risk pregnancy for NTDs, characterized by a history of NTD. Four groups were analyzed: folic acid supplementation (4 mg or 4000 mcg), other vitamins (A,D,B1,B2,B6,C and nicotinamide), folic acid (4 mg or 4000 mcg) plus other vitamins, or neither. 27 women had children with NTD (6 in the folic acid groups, and 21 in the other vitamins or neither). This showed a “72% protective effect,” which kickstarted several other studies and guidelines.²⁰
  • One limitation to this study is that is only reviewed recurrent NTDs, not first occurrences.¹⁷
• From 1984-1991, 3056 babies were observed to see if there was a NTD. Hungarian women who entered this study did not have a history of NTD, but may have had a family history (41 total women). Two groups were studied: supplementation with 800 mcg folic acid and no PNV. 10 babies with NTD were observed (1 supplement group, 9 in the unsupplemented group). This study concluded that there is a statistically significant reduction in NTD in women who were supplemented with folic acid.²¹
  • A limitation of this study is that these women were only from Hungary, which may have different conditions than the U.S. when it comes to folate and/or folic acid intake.¹⁷
• A meta analysis was completed to observe 8 control case studies. Periconceptual folic acid supplementation (300-800 mcg) was effective at reducing NTD risk by 33%.⁸
• Similarly to the above, a metaanalysis of 3 cohort studies and 1 randomized controlled trial (RCT), folic acid supplementation prior to conception reduced the risk of NTD by 62%.
• Two observational studies were conducted in 1993 and 1994 and found that increasing dietary folate to a median level of 300 mcg in women who were unsupplemented reduced the risk of NTDs. NTD risk decreased between 100-400 mcg of dietary folate, but no reduction of risk was noted with >400 mcg. However, this study had a small sample size.⁷
• A randomized trial conducted in 1992 assessed periconceptual folate supplementation of 800 mcg. 4753 women were enrolled. No NTDs were found in the group taking 800 mcg of folate. 6 women were found to have NTDs in the group receiving a trace supplement.⁷
• Four studies conducted in 1976, 1981, 1993, and 1995 found that erythrocyte folate levels were higher in women with children who did not have an NTD compared to those who did. 
• Unrelated to NTDs, but interesting nevertheless, a study did find that supplementation with folic acid in women who did not ovulate or had irregular ovulation cycles had improved fertility. Specifically women who did not ovulate and were infertile had a reduction in these cyclical abnormalities by 59%.⁸ 
• A systemic review was completed in 2023 for the United States Preventative Services Task Force (USPSTF). The evidence found supported preexisting evidence that folic acid supplementation reduces the risk of NTDs.²²
• Folic acid not only can help reduce the risk of NTDs but can also help prevent adverse outcomes in pregnancy, such as preterm birth, anemia, miscarriages, and growth restriction in utero.24

Folic acid is the only source, confirmed in evidence, that can prevent neural tube defects. The downstream metabolite of folic acid, 5-MTHF, is part of a mechanism that is not completely understood, which contributes to the formation of the neural tube. The neural tube in an infant, often beginning very early on in pregnancy around weeks 3-4, is the precursor to the formation of our nervous system (spinal cord, brain). A very important process!

How much folic acid do pregnant women need to decrease the risk of NTDs? 

• The American Academy of Obstetricians and Gynecologists (ACOG) recommends 600 mcg DFE of folic acid (353 mcg of folic acid).¹ 
• The United States Preventative Services Task Force (USPSTF) recommends 400 – 800 mcg of folic acid.² 
• “The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 mcg) of folic acid.”²³
• In 1998, the U.S. started to fortify foods with folic acid after large RCTs evidence started to emerge. The idea of this was to help reduce the risk of NTDs in mothers who had an unplanned pregnancy and those who did not take folic acid supplementation early on pregnancy (since folic acid is important even 4 weeks prior to conception).¹⁹
  • One narrative review (recently published as of May 2026) compares folate and folic acid, and critically reviews the fortification of foods with folic acid mandated by national health organizations.¹⁹
    • Raises concerns for food fortification along with supplementation could increase folic acid above the upper tolerable limit (UL) (1000 mcg).
    • The Cochrane review, which is a resource that completes meta-analyses or systemic reviews, holds a low confidence that food fortified with folic acid reduces the risk of NTDs. And that there is no data on the possible effects of food fortification. 
    • They note that more systemic reviews need to be completed when it comes to food fortified with folic acid. 

As mentioned earlier, folic acid is the only studied version of folate that was shown to prevent NTD. It is not entirely known why exactly folic acid was shown to reduce NTDs. It can be theorized that it is because folic acid is converted to 5-MTHF used for neural tube formation, but that is not exactly what is known, rather hypothesized. However, that does not mean that there is no evidence that shows the benefits of the most active form of folate in a supplement (5-methyltetrahydrofolate or 5-MTHF). See some of the narrative reviews below.

What about supplementation with 5-MTHF (instead of folic acid)? 

There are some concerns that folic acid, given it is synthetic and requires lots of steps to break down to 5-MTHF, creates a lot of room for error when it comes to the metabolism process. And it has been found that 5-MTHF supplementation can maintain erythrocyte and serum folate levels similarly to folic acid supplementation.^25,26 It also can reduce homocysteine levels as efficiently as folic acid.¹⁵ 5-MTHF currently has no upper tolerable limit.¹⁷

A systemic review and meta analysis published in 2025 found that the active form of folate can increase both erythrocyte and plasma folate. Notably, they also found that the active form of folate decreases UMFA, and potentially less adverse maternal outcomes. Some limitations of this study included: short duration of the studies observed, variation in folic acid supplementation, and geographic variations/factors.²⁶ 

But, there are currently no randomized controlled trials on 5-MTHF supplementation for reduction of risk of NTDs, and likely for a good reason. That would require women to take 5-MTHF over the known agent to prevent NTDs, folic acid, as the intervention group. This poses an ethical dilemma. Why would 5-MTHF be preferred over folic acid if there is a large study showing its prevention of neural tube defects? Can folate do the same? 

However, there are a few narrative reviews and observational studies that dive into this. Narrative review studies are a type of lower tier evidence, but interesting to dive into. They are worth reading, but are not made into guidelines because they are not reviewed, trials, and can be based on expert opinion. 

• One author commented that 5-MTHF was superior to folic acid due to a few reasons¹⁰:
  • High doses of folic acid can lead to unmetabolized folic acid. 5-MTHF has shown to prevent this effect. 
  • “UMFA may compete with natural folate for the folate transporter and folate receptor for participation in the metabolic cycles.” 
  • UMFA can be found in cord blood of the infant. 
  • Concerns for limited availability of folate availability with MTHFR polymorphisms  if folic acid is taken (however this was shown in a study above that folic acid supplementation with those with MTHFR can remedy negative effects of elevated homocysteine). 
  • 5-MTHF was shown in one study to reduce homocysteine levels in patients with C677T gene variants as effectively as folic acid. However several limitations of this study were found, with one being a very small sample size (n=20). 
  • 5-MTHF is preferred for those with polymorphisms. 
  • They highlight that one retrospective study found that women who took a vitamin B complex (5-MTHF, vitamin B12, and vitamin B6) compared to those who just took folic acid had a higher chance of pregnancy and live births.^10,11
  • 5-MTHF has improved fertility with supplementation over high dose folic acid.
• A few researchers from the Georgetown Medical Review highlighted that¹³:
  • Highlighted a study that found that UMFA is detectable at >200 mcg^13,14
  • Taking 5-MTHF can reduce the potential for masking of a B12 deficiency.
  • 5-MTHF can help reduce risk of UMFA (although the effects of this are still unknown).
  • See their article (reference 13) showing a table of their proposed benefits and risk of both folic acid and 5-MTHF.
• Reviewing folic acid, folinic acid, and 5-MTHF:
  • The one-carbon metabolism cycle is a part of the process of methylation, which turns on and off genes, leading to expression of various proteins. Changes in these methylation processes can affect the development of a growing baby.
• One narrative review was specifically written to highlight the use of 5-MTHF for prevention of NTDs:
  • 5-MTHF would need to be further studied in order to recommend it as a preventative supplement to reduce risk of NTD.¹² 
• 5-MTHF supplementation to replace folic acid?¹⁷
  • 5-MTHF is found in cord blood of an infant
  • Supplementation with other cofactors (vitamin B12, zinc, B2, B6, and choline) may also potentially lead to decreased risks of errors in the one-carbon folate cycle. 
  • It is important for women TTC to take folate of at least 400 mcg 4 weeks prior to and 12 weeks after conception. 
  • Improving folate status can also help prevent other congenital anomalies such as cleft lip/palate and congenital heart defects.
  • Polymorphisms (gene variants like we discussed above) can lead to more congenital defects.
  • Folic acid supplementation may mask a vitamin B12 deficiency. 
  • Multiple studies have shown that low dietary folate can increase the risk of NTDs. Supplementation with folic acid reduced the risk of NTD, which this particular review attributes to increased 5-MTHF from the folic acid intake.
  • UMFA is detected in women who take folic acid supplementation but not in women who take 5-MTHF supplements. 
  • 5-MTHF supplementation (specifically of 416 mcg) can “improve or maintain RBC folate concentrations” better than folic acid. 

Summary

No matter the form of folate, it is clear that our bodies need folate to complete complex, vital processes. With diet alone, even if rich in folate, it is hard to achieve good folate levels, especially in pregnancy. Therefore, it is recommended to supplement with folic acid.⁸

There are some concerns about those with MTHFR mutations, and their inability to metabolize and process the active forms of folate as quickly needed for fetal development and other bodily processes. There are also concerns about unmetabolized folic acid (UMFA) in this population that could have consequences. Whether or not UMFA is an issue is still unknown. But, the larger concern is the amount of active form of folate needed to develop a healthy baby. As many dietitians will explain, we likely do not get enough nutrients for pregnancy in diet alone.⁸ Some women may not get enough folate in their diet, so supplements help reach the goal amount needed. 

Supplements containing 5-MTHF are more and more common, and could provide the same benefits as folic acid. Even though there are no trials highlighting the same benefits of 5-MTHF as folic acid when it comes to neural tube defects, it would be difficult to attempt one as it poses an ethical issue. This would require women to take 5-MTHF and folic acid in another group, even though folic acid has been shown for decades to prevent NTDs. That being said, many women have probably only taken 5-MTHF for their pregnancies since it is more widely used in a prenatal vitamin. A retrospective study may be coming our way… It may take many years of new research and evidence for a change like this to occur and change guidelines if evidence shows 5-MTHF can prevent NTDs like folic acid. 

But here’s the bottom line: 

Currently evidence holds that only folic acid supplementation of at least 400 mcg of folic acid can prevent NTDs, not 5-methytetrahydrofolate (5-MTHF) or folinic acid (calcium folinate). These have not been tested. Additionally, it is not entirely known why folic acid decreases NTDs. Through deductive reasoning, you could conclude that folic acid leads to increases in plasma levels of 5-MTHF, but we cannot say with certainty that folic acid doesn’t play another role in preventing NTDs. 

When it comes to taking a supplement for preconception, pregnancy, and postpartum/breastfeeding it will be key to discuss with your health care provider about what is needed for you. Some providers will recommend taking folate and folic acid in tandem. We hope this information also helps inform you to be empowered to ask questions and make the right choices. 

If you would like to know some supplement brands that make just folic acid, you can see these on our supplements page.

Best,

The PA Sisters

Medical Disclaimer: The PA Sisters are licensed Physician Assistants in the state of Texas, but the content on this blog is intended for informational and educational purposes only. Nothing here constitutes medical advice, diagnosis, or treatment under Texas law or any other applicable law. Always consult your own licensed healthcare provider before making any health-related decisions. Read our full Medical Disclaimer.

References

1. American College of Obstetricians and Gynecologists. Folic acid supplementation: a foundation for lifelong health. Published March 26, 2026.
2. US Preventive Services Task Force. Folic acid supplementation to prevent neural tube defects: preventive medication. Published August 1, 2023.
3. Saldanha LG, Dwyer JT, Haggans CJ, Mills JL, Potischman N. Perspective: Time to Resolve Confusion on Folate Amounts, Units, and Forms in Prenatal Supplements. Adv Nutr. 2020;11(4):753-759.
4. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/ 
5. Rudolf Then, Thymidylate Synthase*, Editor(s): S.J. Enna, David B. Bylund, xPharm: The Comprehensive Pharmacology Reference, Elsevier, 2007, Pages 1-10, ISBN 9780080552323, https://doi.org/10.1016/B978-008055232-3.60521-5.
6. Minich DM, Brown BI. A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients. 2019;11(9):2073. Published 2019 Sep 3. doi:10.3390/nu11092073
7. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998. 8, Folate.
8. Thaler CJ. Folate Metabolism and Human Reproduction. Geburtshilfe Frauenheilkd. 2014;74(9):845-851. doi:10.1055/s-0034-1383058
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