Why Pregnant Women Are Avoiding Folic Acid Supplements
History of Folic Acid
In 1931, Dr. Lucy Wells, a British pathologist, went to Bombay to investigate macrocytic anemia in pregnancy, which was prevalent in female textile workers. She found that the anemia was most frequent in poorer populations with diets deficient in protein, fruit, and vegetables. This led Wills to study the effects of changes in diet on the macrocytic anemia of albino rats. She discovered that the anemia was prevented by yeast added to a diet otherwise lacking B vitamins
In 1941, folate was first isolated from spinach and received the name "folic acid." This was the same vitamin that was helpful in reversing anemia in those lab rats in Dr. Wells's study.
In 1943, folic acid was first chemically manufactured by Bob Stokstad (working at Lederle Laboratories American Cyanid Company) in Pearl River, New York. This synthetic form was different than the natural folate found in foods, however, in it's chemical structure. So at that point, "folic acid" became used to denote the fully oxidized chemical compound, not present in natural foods.
(Currently, the term "folate" is used to denote the large group of compounds possessing the same vitamin activity and includes natural folates and folic acid.)
In 1965, after many years of study, the relationship between apparent folate deficiency and NTD (neural tube defects) occurrence was hypothesized. The British Medical Research Council conducted a randomized control trial and found that women with a previous history of a pregnancy affected by NTD reduced their recurrence risk by 70% by taking 4000 micrograms (µg) of folic acid daily.
In 1991, the Centers for Disease Control (CDC) recommended that women with a history of a prior NTD-affected pregnancy should consume 4,000 micrograms of folic acid daily starting at the time they begin planning a pregnancy. The following year, the U.S. Public Health Service began recommending that all women of childbearing age consume 400 micrograms of folic acid daily through fortification, supplementation, and diet to prevent NTDs.
In 1998, the United States authorized mandatory fortification of enriched cereal grain products with folic acid. The U.S. program adds 140 µg of folic acid per 100 g of enriched cereal grain product and has been estimated to provide 100–200 µg of folic acid per day to women of childbearing age.
Folic Acid for Fetal Development
It's been well documented that folic acid prevents NTDs (neural tube defects). These are defects of the brain, spine, and spinal cord, most notably spina bifida and anencephaly.
Since the FDA began mandatory fortification of enriched cereal-grain products, folic acid deficiency has dropped significantly. This 2005 article from the Journal of the American College of Nutrition states, "Mandatory folic acid fortification led to significant increases in both serum and erythrocyte folate concentrations in all sex and age groups. In the overall study population the mean serum folate concentration increased more than two-fold (136%), from 11.4 nmol/L to 26.9 nmol/L." Folic acid does prevent the anemia associated with NTDs.
It also appears to help prevent some other birth defects and complications too. This article from the "Reviews in Obstetrics and Gynecology" states that in addition to the prevent of NTDs, folic acid also helps to prevent congenital heart disease, oral clefts, preterm birth and placenta-related complications.
Problems Associated with Excessive Folic Acid
With all of the good that folic acid seems to afford a pregnant woman, it is not without risk for some women.
A Johns Hopkins study that was released in 2016 found that too much folic acid can have detriments and has been associated with autism, a neurodevelopmental condition characterized by social impairment, abnormal communication, and repetitive or unusual behavior
M. Daniele Fallin, Director of the School of Public Health's Wendy Klag Center for Autism and Developmental Disabilities, was the study's senior author. She and her research team followed 1,391 mothers between 1998 and 2013, following each for several years. They found that if folate levels in mothers were extremely high, as drawn shortly after giving birth, their babies chance of developing autism doubled.
The team also tested vitamin B12 levels in each of the mothers. Very high vitamin B12 levels in new moms were also potentially considered harmful, tripling the risk that her offspring would develop an autism spectrum disorder. If both levels were extremely high, the risk that a child develops the condition increases 17.6 times.
Associations with Cancer
Although not directly related to pregnancy, the general population needs to be aware of an association between high folic acid levels and cancer. Studies have shown a correspondence of excessive folic acid with various cancers. High folic acid was found to be connected with prostate cancer, colon cancer, an increase in overall cancer rates, and promotion of existing pre-malignant lesions.
What Causes High Levels of Folate and Vitamin B12?
Researchers from the Johns Hopkins study were quick to point out that the cause for abnormally high folate and vitamin B12 is unclear. They were not exactly sure why some women had such high blood serum levels. They hypothesized that it could be that the studied women consumed too many folic acid-fortified foods or took too many supplements. Or, they say, it could be that some women are genetically predisposed to absorbing greater quantities of folate and vitamin B12 or metabolizing them slower, leading to the excess. Or it could be a combination of the two.
MTHFR Gene Mutation
High Folate Levels
When the Johns Hopkins researchers made reference to a "genetic predisposition" to folate absorption or metabolism abnormalities, essentially they were referring to an MTHFR gene mutation.
MTHFR stands for Methylenetetrahydrofolate Reductase. It is an enzyme that adds a methyl group to folic acid to make it usable by the body (because, if you'll remember, folic acid is a synthetic compound.) If someone has an MTHFR gene mutation, the enzyme is defective.
MTHFR is needed for DNA reproduction and is essential for folate metabolism. So, if a person has an MTHFR mutation, folic acid is not fully utilized, nor is it correctly "methylated" in the liver (and turned into the usable form of "folate"). This can result in a high level of serum folic acid because it is essentially not metabolized.
It is this unmetabolized folic acid that is the problem.
MTHFR mutations are quite prevalent. In the United States, it is estimated that up to 60% of the population are "intermediate metabolizers" of folic acid. They have a heterozygous mutation (received from one parent), and may have some issues processing folic acid. And it's estimated that 25% of the population has a homozygous mutation (received from both parents). This mutation is very problematic due to the great likelihood that the person metabolizes folic acid very little. (A homozygous mutation results in an up to 90% decrease in the ability to use folic acid.)
High Vitamin B12 Levels
In addition to inappropriate folic acid metabolism, having an MTHFR gene mutation could also result in abnormally high blood serum levels of vitamin B12. Again, the synthetic form of B12 (cyanocobalamin) is not methylated in the liver correctly, so the conversion to the usable form of B12 (methylcobalamin) is impaired. The synthetic form of vitamin B12 is found in most multi-vitamins and prenatal vitamins.
In the autism research field, Dr. Amy Yasko has not seen an autistic child who did not have one or more MTHFR gene mutations. And because these are hereditary, a mother with an MTHFR mutation is likely to pass along a mutated gene to her offspring. So not only might a mother not process folic acid or vitamin B12 correctly due to her mutation, she might also pass along the MTHFR gene to her child.
How Do You Know if You Have an MTHFR gene mutation?
One would not know for sure if they have an MTHFR mutation unless they were tested. If you're curious about whether or not you carry a mutated gene, 23 and Me is a company that provides DNA testing via saliva sample. It gives results regarding heritage as well as genetic makeup. Once results are emailed to you, you can go to Genetic Genie which will interpret your methylation genetics by looking at the 23 and Me raw data for free.
However, women need not test for this mutation in order to take proper precautions; precautions which are also without risk and are, perhaps, even more nourishing for the pregnant body and growing fetus.
How Can Pregnant Women Be Sure to Get the Correct Amount of Folate and Vitamin B12?
Daniele Fallin, from the aforementioned Johns Hopkins study, carefully points out that pregnant women and those trying to conceive absolutely need adequate levels of folate to ensure a healthy pregnancy and fetal development. She says, "Using vitamin supplementation, particularly during very early pregnancy, appears to be protective for autism—women who supplement have a lower risk of autism in their child." However, she goes on to say, "You definitely don’t want to be too low in folate. But there may be a concern if you’re way too high."
So, how can pregnant women reach the "sweet spot" where they have enough circulating folate (and vitamin B12) but not too much, especially if they're unsure whether or not they have an MTHFR mutation?
Methylated Form of Supplements:
Authors of the previously mentioned article from "Review in Obstetrics and Gynecology" recommend supplementing with methylated forms of vitamins.
"Based on the high prevalence of MTHFR genetic polymorphisms in the general population and concerns about reduced enzymatic activity and, therefore, less biologically available l-methylfolate, newer research in this area has focused on supplementation with l-methylfolate rather than folic acid as a means of preventing folate-related pathology."
"Although folic acid supplementation to supraphysiologic levels has demonstrated many of the benefits to pregnant women and fetuses [...] the potential risk of high-dose folate supplementation must also be considered. [...] concerns have been raised about the potentially untoward effects of unmetabolized synthetic folic acid with regard to cancer, depression, and cognitive impairment. With all these concerns, early data suggest supplementation with l-methylfolate rather than folic acid may mitigate these risks."
Methylfolate: Women can start by supplementing with folate that is fully absorbed, natural, and not synthetic. Methylfolate is the source to look for in prenatal vitamins or in stand alone supplements. (Look for products that contain the Metafolin brand, folinic acid, or list “5-methyltetrahydrofolate” or “5-MTHF”.) This is important because most prenatals do NOT contain this form and instead contain the synthetic folic acid.
The RDI of folate is between 500-600mcg per day for women who are breastfeeding, pregnant, or trying to conceive. However, some experts believe that women should supplement with 800-1200mcg per day of methylfolate starting several months before trying to conceive and into the pregnancy.
Methylcobalamin: Most over-the-counter multivitamins and prenatals contain synthetic cyanocobalamin. Methylcobalamin is the natural, bioavailable form of vitamin B12. It is readily absorbed. This can also be purchased as a stand-alone supplement or even combined with methylfolate. (If a multivitamin contains methylfolate, it typically also contains methylcobalamin.)
Food Sources of Folate
Consuming foods rich in natural folates also helps the body obtain good folate stores. These are readily absorbed and would not contribute to excessive circulating levels since they contain the non-synthetic version of folate.
Some Natural Food Sources of Folate
Folate (in mcg)
1 cup Chicken Liver
1 cup Beef Liver
1 cup Spinach
1 cup Collard Greens
1 cup Romaine Lettuce
1 cup Brussels Sprouts
1 cup Kale
1 cup Asparagus
1 cup Beets
1 cup Green Peas
1 cup Broccoli
1 cup Winter Squash
1 cup Sunflower Seeds
1 cup Hazelnuts
1 cup Sesame Seeds
1 cup Cashews
1 cup Pumpkin Seeds
Undoubtedly, women planning to conceive or who are pregnant absolutely must have adequate folate stores to prevent NTDs in their unborn babies.
Excessive folic acid levels, however, may be detrimental to both the mom and the baby.
Excessive levels may be caused by an unrecognized MTHFR gene mutation.
To get the most absorbable form of folate which would ensure adequate levels but not excessive levels, women may consume methylated versions of both folate (methylfolate) and vitamin B12 (methylcobalamin).
Eating folate-rich foods also helps to naturally boost serum folate levels.
Important Video Discussing The Benefits of Folate Over Folic Acid
Combined Methylfolate/ Methylcobalamin Lozenge
This content is for informational purposes only and does not substitute for formal and individualized diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed medical professional. Do not stop or alter your current course of treatment. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.