Many women are already aware that folate is one of the most important prenatal vitamins to take while pregnant. Without proper levels of this vitamin, the neural tube (which develops into the fetal spinal cord) cannot close, which leads to birth defects like spina bifida and even spontaneous abortion.
So, everyone agrees that adding folate is important to pregnant women’s diet, right?
There is quite a bit of controversy surrounding whether the synthetic version, folic acid, is more harmful than the natural version of folate, especially if you have certain genetic risk factors, like the MTHFR mutation.
So, while pretty much everyone agrees that folate is important, the controversy surrounding folate versus folic acid has caused confusion about how to choose the best prenatal vitamin. This post will cover:
- What is folate?
- Why is folate for fertility?
- What is the folate versus folic acid controversy?
- How does the MTHFR genetic variation factor into the controversy?
What is folate?
“Folate” broadly refers to both the synthetic and natural versions of the vitamin.
The synthetic version, or folic acid, is popularly used in vitamins including prenatal vitamins and is used by health agencies to fortify grains, cereal, and bread.
The dietary forms of folate are monoglutamate folate and polyglutamate folate, which are found in leafy greens and legumes.
When you ingest biological substances such as sugars and nutrients, your body has to transform them (AKA metabolize them) into a form that can be used for energy. Cells in the intestines readily transform dietary folate into a form of folate called 5-methyltetrahydrofolate (5-MTHF). This version of the vitamin you see as “folate” or “natural folate” supplement in the store, vitamin that circulates in the blood.
Why does folate matter for my fertility?
Once in the blood, 5-MTHF essentially acts as a molecule bus that transports different passengers, methyl groups and carbon groups, and drops them off at different stops:
- The homocysteine stop: 5-MTHF can drop off methyl groups at the molecule homocysteine. This will then transform homocysteine into methionine, which is an important building block for proteins.
This is important because when folate levels are low, too much homocysteine builds up and doesn’t get converted to methionine, and this extra homocysteine can be toxic to cells.
- The DNA synthesis stop: 5-MTHF can drop off carbon groups to make purines and pyrimidines (the building blocks of DNA).
Both processes are crucial for the initial development of the fetus and for the neural tube, which occurs during the first few weeks of pregnancy. For this reason, women are encouraged to take prenatal vitamins even before becoming pregnant so that there is already sufficient folate present at the time of conception.
Another important point is that folate isn’t just important for mothers-to-be, but also for fathers-to-be. Because folate is important for making DNA and protein, it’s also important for making healthy sperm1.
Why does folate matter for my overall health?
Building proteins and DNA is instrumental for many biological processes over the course of the entire lifespan, not just when a woman is trying to get pregnant. So, folate is important for your overall well-being, not just during pregnancy. In fact, folate deficiency is linked to anemia2 and depression3.
How is folic acid different from folate?
If 5-MTHF is a molecule bus, then folic acid is the same bus but with a chemical wheel boot. It can do all the things that 5-MTHF does, but it’s basically useless unless the boot is removed.
So, how does your body get rid of the boot? It takes two steps:
- Step one: convert folic acid into tetrahydrofolate using the liver enzyme dihydrofolate reductase.
- Step two: convert tetrahydrofolate into the bioactive 5-MTHF using another liver enzyme methylenetetrahydrofolate reductase (MTHFR).
So, then what’s the problem with using folic acid?
When both of these liver enzymes are available to do these chemical transformations—great!—the boot is removed and folic acid is able to step in and do the things 5-MTHF does.
Here’s the problem: these enzymes aren’t always ready for how much folic acid you’re ingesting.
In fact, during step 1, it’s relatively easy for that enzyme to get overwhelmed and slow down how quickly it can process folic acid4. This is problematic because this synthetic version is widespread in grains, cereals, and breads as well as in standard prenatal vitamins and multivitamins. When the enzyme in step 1 is overwhelmed, unmetabolized folic acid (UMFA) accumulates, which has been linked to risk for cancer (discussed below)
Is folic acid dangerous for people with MTHFR mutation?
During step two, the enzyme MTHFR is important for finally transforming folic acid into 5-MTHF. The problem is that different genetic variants of MTHFR can impact how well this enzyme works.
DNA is basically a string of nucleotides, which are the building blocks of DNA. The MTHFR gene is a very long line of these nucleotides, and the nucleotide we need to focus on is nucleotide #677. Here is where the polymorphism, or genetic swap in nucleotides, can occur.
If you have the C677C variant, MTHFR is encoded normally.
If you have the C677T variant, MTHFR is working at about 65% of normal activity.
If you have the T677T, MTHFR is working at about 30% of normal activity.
So, even though it’s one single nucleotide, it has a profound influence on how well the body is able to process folic acid. If you have the C677T or T677T variant, then this means you’re at a higher risk for UMFA build up which may potentially factor into an increased risk for cancer and vascular disease 5.
The C677T and T677T variant are also associated with increased risk of neural tube defects. Interestingly, individuals with the T677T variant (the one with those lowest MTHFR enzyme activity) experience a boost in folate levels when they take a dose of 5-MTHF supplementation but not folic acid supplementation. It should be noted that the study only administered how folate levels looked after one dose of treatment, not a daily supplementation, so it’s not clear how meaningful this is for taking a daily multivitamin or eating a diet heavy in folic acid 6.
Should I switch to using 5-MTHF supplementation instead of folic acid?
To answer that question, you’re going to have to think about your own personal risk assessment. Here’s why: there is good clinical evidence that 5-MTHF and folic acid are equally beneficial (and some evidence that 5-MTHF is even better) in improving folate status in women7. The only problem is, showing that 5-MTHF is a good way to improve folate status is NOT the same thing as showing that 5-MTHF prevents neural tube defects.
Low levels of maternal 5-MTHF increase risk for birth defects, and folic acid is likely protecting against these outcomes because of its conversion to 5-MTHF8. BUT, there is no clinical data available to definitively say that supplementing with 5-MTHF is equally as protective as folic acid to prevent neural tube defects. Why is there no data? Because of ethical restrictions.
To really answer this part of the folate versus folic acid debate, scientists would need to randomly assign women to 5-MTHF, folic acid, or placebo
Treatments and compare the resulting number of neural tube defects. In this hypothetical experiment, the placebo condition and potentially even the 5-MTHF condition could seriously endanger the health of women and their babies. Ethically, this experiment is simply not possible.
So, without this experiment, it’s difficult to say for sure that 5-MTHF supplementation is as protective as folic acid to prevent neural tube defects. Because the evidence for folic acid to reduce neural tube defects already exists9, there is a solid case for using it. While the logic for using 5-MTHF is sound, the missing experimental evidence means it’s the riskier choice.
Sidenote: An interesting study compared folic acid and 5-MTHF in women that had recently given birth and were breastfeeding, since these same ethical restrictions don’t exist for this situation. Interestingly, they found that 5-MTHF was more beneficial than folic acid for long-term folate status (both treatments were equally effective for improving transient folate status)10. This is important because women may stop taking prenatal vitamins after they give birth but lactation can reduce folate levels, so supplementing with 5-MTHF may be more beneficial than folic acid for breastfeeding moms.]
The take-home message: 5-MTHF generally seems to be as efficient (if not better) as folic acid supplementation on folate biomarkers in women. But, science cannot definitely tell you what that means for neural tube defects, and that will be a decision you and your doctor can make together.
I want to look at all the evidence myself and decide what to do. What should I look for in the data?
Now that you know more about the controversy, you might be interested in reading up on the clinical evidence yourself so that you can talk to your doctor and make an evidence-based decision—this is always a great idea!
To guide you on your science quest, here are some questions to ask that will help you draw your own conclusions:
- “Did the study use a placebo control?”: This is a really important component to a good experiment. If there is no placebo or control treatment, then there is no way to determine how much the experimental treatment mattered for the outcome.
- “Who were the subjects?”: Some studies will use only men, others only women. Other studies may exclude subjects with the MTHFR mutations. Make note of the study’s subjects because this will influence how relevant the data are to you.
- “How long was the intervention?”: Some studies will measure a one-time folate dose and some studies will administer the treatment for several weeks. These timing differences can affect the magnitude of folate changes observed, so it’s important to take timing into account.
- “Did the study look at plasma or red blood cell folate?”: Answering this question will tell you how important the experiment was for making short-term or long-term folate changes. Short-term changes show up in the plasma folate levels, and long-term folate changes show up in the red blood cell folate levels.
- 5-MTHF: The bioactive version of the vitamin that is readily created from dietary ingestion of folate-rich food by intestinal cells.
- Dihydrofolate reductase: The liver enzyme that takes folic acid and chemically reduces it to tetrahydrofolate.
- Folic acid: The synthetic version of the vitamin found in prenatal vitamins or in most over-the-counter vitamin supplements. It is also added to grains, breads, and cereals.
- Homocysteine: The molecule that folate can convert into methionine, a building block of proteins. Too much homocysteine can be dangerous for cells and is related to the medical condition homocystinuria. Homocysteine and folate are usually inversely related, so if folate levels are low, homocysteine levels are typically high.
- MTHFR mutation: Depending on certain variants of this gene, having either one or two T’s can mean reduced activity of this enzyme.
- Monoglutamate folate & polyglutamate folate: These are naturally occurring forms of folate found in foods like legumes and leafy greens.
- Tetrahydrofolate: the intermediate version of folate between folic acid and 5-MTHF.
- Unmetabolized folic acid: When folic acid cannot be converted into 5-MTHF by the liver, it builds up in the body and is excreted via the urine as unmetabolized folic acid.
- https://www.ncbi.nlm.nih.gov/pubmed/18353905 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/17568057 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/14960902 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/24944062 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/24091066 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/14769778 ↩
- Studies measuring folate status usually measure folate levels in red blood cells—which is indicative of long-term folate status—or in the plasma of blood—which is indicative of short-term folate status. So, if you recently changed your diet, this would show up as a transient change in your plasma folate.
But, if you had a chronic condition that reduced folate levels for several months, it would show up in your red blood cells. One study randomly assigned adult women to 24 weeks of 416 μg of 5-MTHF, 400 μg of folic acid, or placebo (meaning no 5-MTHF or folic acid) treatments. While both interventions increased red blood cell folate levels in comparison to placebo, 5-MTHF supplementation did so to a greater extent than the folic acid supplement. Both interventions did equally well in increasing plasma folate levels in comparison to a placebo. The study also randomized women with the three different MTHFR polymorphisms across all of these groups. So, while either of these treatments can improve folate levels in the short-term, 5-MTHF had a greater impact on long-term folate status[5.https://www.ncbi.nlm.nih.gov/pubmed/16825690 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/23482308 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/24007422 ↩
- https://www.ncbi.nlm.nih.gov/pubmed/16600937 ↩