Two Gene Mutations and Pregnancy: MTHFR and MMADHC 

***Updated May 1, 2021

With all the advances in “modern medicine”, what is known about Hyperemesis Gravidarum (HG) correlates to being in the dark ages. I am hoping that the young science of pharmacogenetics, the study of how the body’s genetic variation determines the response to medications, including vitamins, may give us some clues. One possible relationship where I would like to see more research is determining the extent of HG when our body cannot metabolize the B vitamins that we ingest. Two of the genetic variations that determine this breakdown are known as MTHFR and MMADHC. I’m curious if the extent of nausea and vomiting, the percentage of miscarriages, and possibly even the birth defects being related to Zofran in HG moms have a connection to the variations of these genes.

The MTHFR gene

The genetic mutation that I get asked most about is the MTHFR gene. MTHFR stands for methylenetetrahydrofolate reductase, but is shortened to MTHFR, an acronym that makes everyone laugh. Ultimately it is not funny because it may have devastating consequences if it has just the right mutation. According to Rachel Liberto, RN, “women who test positive for a mutated MTHFR gene, may have a higher risk for miscarriages, preeclampsia, or a baby born with birth defects because homocysteine can build up in our body to toxic levels.” Many studies have proven this to be false, and it still a hot topic among pregnant women.

How many people have this mutation? 

According to Kaiser Permanente, 10-15% of the Caucasian population and 25% of the Latino population have both copies, while up to 50% of people worldwide have at least one variant (also called genotypes). The common MTHFR variants known today are called C677T and A1298C. Fortunately, research shows that having one variant will not cause problems. It’s those with two or more working together that may have detrimental results.

What exactly does the MTHFR gene do? 

In short, the MTHFR breaks down very important vitamins so they can get into our blood and do their job in our bodies, a process called methylation. According to the National Institute of Health “This is important for a chemical reaction involving the vitamin folate, vitamin B9. Folate is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.” These compounds are necessary for preventing neural tube defects among other important processes early in the pregnancy. Another one of its many jobs is helping the body get rid of toxins, which explains why having too much of it can wreak havoc on the body and developing baby. 

Folate, folic acid…what’s the difference?

All pregnant women are told by their doctors to take folic acid supplements while trying to get pregnant as well as during pregnancy to prevent birth defects. Folic acid is the synthetic form of the natural form called folate. In 1998, folic acid was even added to our bread and cereals. Dr. Ben Lynch in his book “Dirty Genes”, says “fortifying our foods with folic acid could be dangerous due to gene mutations. The issue is it’s not the best form of folate to use. The combination of MTHFR and pregnancy really stress the point that you should NOT use folic acid.” 

Dr. Lynch’s opinion, though, conflicts with the CDC who states, “You might have read or heard that folic acid is not safe if you have one or two copies of the MTHFR C677T variant. This is not true! Even if you have one or two copies of the MTHFR C677T variant, your body can safely and effectively process the different types of folate, including folic acid.” 

Does MTHFR affect other vitamins too?

In addition to vitamin B9 (folic acid), testing positive for this mutation also affects other B vitamins including B12 (cyanocobalamin), B6 (pyridoxine) and B2( riboflavin). It’s possible that the connection with MTHFR and HG has to do with its relationship to vitamin B6, as it’s the most scientifically tested and only FDA approved vitamin to help with extreme nausea and vomiting in pregnancy. So far, though, tests hoping to show a connection have come up negative. When Dr. Marlena Fejzo in partnership with the HER Foundation, analyzed the C667T mutation in the MTHFR gene, she did not find an association, but there may be other possible connections that have not been studied yet. She did, however, suggest that I study the MMADHC gene mutations as that looks more promising.

The MMADHC Mutation

The MMADHC converts B12 into one of two other molecules.This process involves the mitochondra and is related to the cell’s energy. According to one study, if there is a genetic mutation, then “These inborn errors result in elevation of either homocysteine or methylmalonic acid, or both, and can lead to human birth defects, including cardiovascular defects and facial dysmorphology.” As I could not find much information on this gene, it is where I will focus researching in the future.

Genetic Testing

Pharmacogenetics is different from the genetic testing that looks at disease states like those  offered through Ancestry.com or 23andme, although 23andme does now offer the MTHFR test as well since they added some health conditions. Those tests look at risks of specific diseases while pharmacogenetics looks at which one of four variations a person has that breaks down the medication. On one end of the four options is the variation of being an “ultrafast metabolizer” in which the medication may shoot through your body super fast, and you’ll never get the response needed from the medication. On the opposite end is the slow metabolizer which means that little of the medication gets metabolized and much of it stays in the body. The same ideas happen with the MTHFR mutation. Using folic acid as the example, depending on the variation, very little will metabolize and too much of the folic acid stays in our body. Through another variation, too much homocysteine may form. Homocysteine is meant to break down to methionine, which is needed for muscle growth and the other processes discussed.

While this is a new science with still so much to learn, MTHFR mutations are now known to be linked to many disorders. The organization Focus for Health states that it is connected to:

• Inflammatory disorders
• Chronic fatigue syndrome
• Some autoimmune disorders
• Cardiovascular disease
• Psychiatric disorders
• High homocysteine levels
• Pregnancy related concerns: 
  • Birth defects 
    • Down’s Syndrome
    • Spina bifida
    • Cleft palate
  • Could HG be related to this too??? 

Even with all of these effects from the MTHFR mutation, there is no evidence relating the MTHFR mutation to HG. The MMADHC needs more research before a determining factor can be made.

Should you get tested for MTHFR?

As of 2016, American College of Obstetricians and Gynecologists (ACOG) and the National Society of Genetic Counselors do not recommend getting tested. They state the meta-analysis, when scientists compare multiple studies on a topic, do not support the mutation leading to birth defects because it is not just the MTHFR mutation that may lead to inadequate levels of folate. They also state that the treatment is the same whether or not there is a mutation: folic acid supplementation. Obviously, Dr. Lynch disagrees, and with many insurance companies now covering the cost of the test, I am curious to see if their advice will change in the future. I personally believe it’s better to be armed with knowledge than to shy away from it. 

What to-do if you have the mutation?

***As alway, check with your doctor before taking any supplements!!!

If you have the MTHFR mutation:

Actually, it’s an easy fix if you are not suffering from HG. The best option is to:

• Eat more dark, leafy, green vegetables. Unfortunately, that’s not easy if you cannot keep food down, so the next best option is to:
• Take B9 in its active form, L-methyl folate. While it’s getting easier to find prenatal vitamins that have the metabolized/active form in it, be sure to read the label carefully. If you want to try 
  • Many folate supplements are available on Amazon with doses ranging from 400 mcg to 15mg. Be aware that there are a variety of strengths as well as salt formulations. The one with the salt glucosamine has not been clinically tested but is more readily available, so we do not know how much of it actually gets absorbed in the body.
  • I have one option in a liquid drop form that is highly recommended from HG women available for you in my store: https://hgpharmacist.com/product/methyl-factors-liquid-drops/. Methyl drops have a B vitamin combination all in their methylated form produced by NutraBiogenesis, a nutraceutical company.*
  • Discuss with your doctor about getting lovenox (Enoxaparin) injections, which breaks down blood clots, to prevent miscarriages if there’s a history of blood clots due to the mutation, as this mom wrote about in an article on Medium. 
• If you know that you have this mutation and have HG, I can partner with your doctor to compound an l-methyl folate patch for you, so that it’s absorbed through the skin.
• For depression related to having the MTHFR mutation, psychiatrists are prescribing a medicinal food called Deplin which is a high dose l-methyl folate. I’d recommend talking to your doctor about this if you have depression along with your HG. Contact the manufacturer if you cannot afford to buy it.
• Interested in connecting the MTHFR mutation with a natural lifestyle? Visit Wellness Mama for more information

***I know a genetics scientist who specializes in pregnancy that says any practitioner who sells you this test is a charlatan out to make money because the large studies show is does not decrease risk of miscarriage or other complications. Personally, I now know that I have the mutation and am grateful my daughters are healthy, which actually supports her statement. While I could not keep down any prenatal vitamins during my pregnancies, but if I have, I would have taken the methylated form of supplements because you’ll still get the benefits of decreased risk of cleft palate and other potential congenital abnormalities.

Where does the folate in our supplements come from?

I had a customer point out to me that the Methyl Drops label states “from folic acid.” For a moment, I was as confused as she was until I thought about it. The only way to get folate in its natural form is directly from nature, from the food we eat. As a supplement, however, it must come from the synthetic form of folic acid. When the label also says methyl folate (or a variation of that), it has already been modified to folate so when it enters our bodies it does not have to be metabolized. I reached out to NutraBiogenesis to confirm this. Here is the response:

“Folate comes from dietary sources and folic acid is a common form found in supplements (as well as fortified foods). Both of these forms enter the folate metabolic pathway at different points (folic acid is converted to DHF before being converted to THF, whereas dietary folate bypasses the DHF step and is converted into THF directly). THF then goes on to be converted to methylated folate (5-MTHF). Methyl Factors also contains 5-MTHF itself.

Something that confuses the picture (on Methyl Factor Drops) is that FDA mandates pertaining to dietary supplements have changed over the years. At times folic acid has appeared as either “folate” or “folic acid” on supplement facts panels. Most recent guidance requires both (thus later this year you will see folate claims refer to a folate quantity with the unit “DFE” or “dietary folate equivalent” AND a folic acid quantity—even though these are referring to the same ingredient).”

Examples of methyl folate labels before and after the FDA changes:

If you have the MMADHC mutation

• While trying to conceive, have “vitamin B12 levels of >300 ng/L. Higher levels may afford a further reduction in risk (of neural tube defects), but this is uncertain”. Vitamin B12 Metabolism during Pregnancy and in Embryonic Mouse Models. 

Getting The MTHFR Test

If you’re interested in having the MTHFR gene test done, it’s an easy cheek swab or a saliva test. I have two options for you in the USA and am connecting with a lab in Canada too.

• Many insurances are covering this test along with a panel of dozens of other genes. I can check with your plan and then partner with your doctor. The results will then get sent to your doctor’s office and you follow up with them. In this case, there are no out of pocket costs for you or your provider. Email me directly at: info@hgpharmacist.com to get started.
• If your insurance plan does not cover the test or if you do not have insurance, I have a cash paying option in my store: https://hgpharmacist.com/shop/ The results get sent to me, and I’ll share them with you.

Want to know more about what our government has to say about the MTHFR gene? Go to: https://rarediseases.info.nih.gov/diseases/10953/mthfr-gene-mutation. I find it funny that this is classified under “Rare Diseases” when we know so many people have this mutation!

Please email info@hgpharmacist.com with questions or comments, as I always learn from your feedback.