The Dangers of UMFA in Pregnancy

UMFA or unmetabolized folic acid is something that has been popping up on research radars more and more frequently in recent years. The combination of food fortifed with folic acid, multivitamin use, the popularity of B complex supplements for energy, and the standard practice of hyper-dosing women with at-risk pregnancies has led to UMFA becoming a common problem. Last week we discussed the remarkable results methyl folate produced in couples with infertility relative to the current standard of care, which is supplementing with folic acid. This week, I’d like to talk about the risks of too much unmetabolized folic acid or UMFA during pregnancy.

First, Let’s Talk Useable Folate

One very wisely designed study published in the American Journal of Clinical Nutrition, compared serum and red blood cell levels of total folate, 5-LMTHF, UMFA, and MeFox which is a methyl folate oxidation product – kind of the 5-LMTHF version of UMFA. The reason I call this study design “wise” is that it gives us a good window into what is actually happening here. Serum levels test the amounts in the fluid part of the blood, which is not yet inside the cells. This isn’t really a functional space for folate – it’s been absorbed digestively, but hasn’t reached useful cellular tissues yet. Red blood cell levels, however, measure the amount that is actually inside of the cell spaces and therefore doing something useful. This study didn’t differentiate between MTHFR or non-MTHFR, or at different forms of folate intake. It simply compares two different doses of folic acid.

One group received about 1.1 mg of folic acid in their prenatal vitamins. The other group received the prenatal vitamin amount plus an additional 4 mg to bring the total to 5.1 mg, or 5100 mcg of folic acid.

What they found in this study, was that the RBC folate level, which is the functional folate, didn’t differ significantly between the two groups. The high-dose folate group did have higher serum levels of total folate, UMFA, and even 5-LMTHF. Other parameters didn’t differ significantly.

The researchers came to the conclusion that there was some kind of tissue saturation happening, where more folate just can’t get into the cells, which makes sense. They also suggest that higher UMFA concentrations in the women receiving the high-dose folic acid indicates that these doses are “supraphysiologic.” That is a fancy way of saying the dose is just too high.

So What is All that UMFA Doing In Pregnancy?

Another study, also published in the American Journal of Clinical Nutrition, studied UMFA levels in cord blood relative to autism spectrum disorder. Cord blood is the blood that remains in the placenta and the attached umbilical cord after delivery.

This study found that babies in the highest quartile of UMFA percentages in the cord blood had the highest risks for autism spectrum disorder. This effect was highest in black babies and significantly correlated with race. This correlation did not apply to the concentrations of 5-MTH or to serum total folate.

Another study, published in the Journal of Allergy and Clinical Immunology In Practice, looked at the association between UMFA levels and food sensitivity and food allergy. This study tested total folate, 5-MTHF, and UMFA levels at birth and again in early childhood.

The researchers found that of 1394 children tested, 507 were found to have food sensitivities and 78 had food allergies. In those children who developed food allergies, the average total folate concentrations at birth were lower and the UMFA levels at birth were higher. Higher UMFA levels later on in childhood didn’t seem to have this same association.

I will quote from the conclusion of this study. “Higher concentrations of UMFA at birth were associated with the development of food allergies, which may be due to increased exposure to synthetic folic acid in utero.”

What To Make Of This?

These are just a few studies and so we really can’t, as much as we might like to, draw sweeping conclusions from them, but it certainly gives us some compelling evidence that too much of what is supposed to be a good thing, can rapidly become a bad thing.

Because we, with MTHFR polymorphisms, are more susceptible to problems associated with folic acid, I think it is important to have an informed and complete conversation with your health care practitioners about the risks of folic acid supplementation in pregnancy for us specifically, and the viable, albeit less well-researched option of supplementing with 5-LMTHF instead.

Links to the research studies I’ve talked about in this podcast are supplied in the complete show notes at tohealthwiththat.com, so if you’re planning a visit to your OB/GYN or midwife, go armed with research to show them.

Thank you so much for listening today and please make sure you’re signed up for our email list – the email list will be the first to know about new courses, programs, and freebies for MTHFR folks.

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The Harm That 5mg Folic Acid Can Do For MTHFR Fertility

This week I wanted to diverge on subjects a bit just because a very relevant question came up in the MTHFR community, This is such an important issue that I want to make sure it gets the attention it deserves.

One of our members in Genetic Rockstars is pregnant and her midwife is recommending 5000 mcg folic acid in spite of her MTHFR issue.  This is a common question because 5000 mcg folic acid is standard practice in many fertility centers and medical offices for pregnancies that are considered in any way at risk.

Like everything else involving MTHFR, research is limited but I do want to deep dive into a couple of relevant studies.

The most important piece of research to take to your midwife or fertility practitioner is a study published in the Journal of Assisted Reproduction and Genetics in 2018.

This study followed 33 couples in which one or both of the partners had an MTHR polymorphism who had fertility problems lasting at least 4 years.  This could include recurrent fetal loss, premature ovarian failure, or abnormal sperm parameters – so bear in mind this could be the mother or the father who has MTHFR issues. Two-thirds of these couples had previously failed assisted reproductive technology attempts.

Most of the women in this study had been previously treated, unsuccessfully, with 5000 mcg (or 5 mg) folic acid.

The couples in this study were given 600 mcg 5-LMTH, which is the active form of folate, for four months before attempting conception or starting another round of assisted fertility treatment. This four-month period was chosen to allow for a complete cycle of spermatogenesis, which is approximately 74 days.

The results of this one simple intervention were, in my opinion, absolutely astounding. Of the 33 couples:

  • 2 were still in treatment at the date of reporting.
  • 13 couples conceived spontaneously (this is after four years of unsuccessful reproductive attempts)
  • 14 achieved successful pregnancies using ART (assisted reproductive technology). ART typically refers to IVF or in-vitro fertilization. 
  • 3 couples did not achieve successful pregnancies.
  • 1 couple failed to report back.

I am going to read the conclusion of this research article verbatim because frankly, I couldn’t sum it up better.

“The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100–200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).”

Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet. 2018;35(8):1431-1435. doi:10.1007/s10815-018-1225-2

The most startling result of this research, I feel, is the tremendous number of couples who conceived spontaneously after a simple few-month intervention with 5-LMTHF. Imagine the amount of heartache, expense, and medical intervention that could be avoided if 5-LMTHF became the standard of care?

The other issue considered here is something called Unmetabolized Folic Acid Syndrome, which has been demonstrated in  “wild type” people to cause pseudo-MTHFR. In pseudo-MTHFR, people who have fully functioning MTHFR enzymes have both high levels of unmetabolized folic acid and high levels of homocysteine in their blood. In people with an MTHFR deficiency, UMFA blocks the entry of folates into the folate cycle and further impairs the capacity of their already struggling MTHFR enzymes.

Unmetabolized Folic Acid has also been implicated in promoting colorectal and prostate cancer. And folic acid itself shows poor clinical success and in some cases, it tests worse than placebo in reducing homocysteine levels or downstream measures of cardiac health.

Next week I’d like to talk about some of the issues that have been linked to high levels of unmetabolized folic acid in pregnant mothers and the problems that travel downstream to those unborn children. If you haven’t done so already, please sign up to the email list on tohealthwiththat.com, or join the MTHFR community Genetic Rockstars at community.tohealthwiththat.com. I have big plans this year for courses and I want you to be the first to know.

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S2E9: MTHFR Questions

I love it when listeners leave me questions so here is this month’s roundup!

I don’t have a doctor that advises me about MTHFR. A mental health provider suspected the mutation because of years of resistant depression. She did a swab to test genetics for specific medication absorption which included MTHFR testing.we found that I have compound heterozygous mutations. I’ve been on high dose methyl folate and B12 for a few years and wonder if I should be getting regular tests for levels etc. where should I go? I have researched the topic myself online but it’s very confusing and there seems to be no general consensus. Can you help me? Thank you,

– Jamie L

This is a great question, Jamie because so many MTHFR folks are out there doing it on their own. Unfortunately, online and between practitioners, there is absolutely no consensus on the best way to do this, so really it comes down to finding the right way for you.

I notice you mention methylfolate and B12 and that is great, but make sure you’re taking the other B vitamins as well because they are all necessary for this to work – especially riboflavin. Also, if you’ve been taking high doses of methylfolate without other Bs, then cut your dose down before you start them because the dose might be too high once you get the other pieces of the puzzle in there.

In terms of testing, the things we want to look at specifically for MTHFR are folate, B12, and homocysteine. Testing every couple of years is fine. Testing folate is complicated because unmetabolized folic acid can be mixed into your total so the test isn’t so valuable except to show us trends (like it’s getting higher or it’s getting lower). B12 testing is straightforward as is homocysteine testing and if you aren’t familiar with homocysteine, check out Season 1, Episode 40: Homocysteine by The Numbers.

Outside of testing, the biggest determinant of whether or not you’re on track is your symptoms. How are you actually doing? If you’re not where you want to be, then maybe it’s time to work with a practitioner who has knowledge about MTHFR and can help you on your path.

Hi! I have an 8 year old boy. He was diagnosed ADHD at the age of 6. We started him on methylphenidates at age 7. We have tried nearly all of them and none of them agreed with him. We had gene testing done earlier this year and MTHFR came back as “Low to Intermediate activity”. Majority of the ADHD medications came back with lower odds of response. What do I do with this information? We have family history of bipolar and anxiety disorders. The adhd medications really brought out a lot of anxiety in my child. He is very competitive. He is obsessive. My son has a terrible issue with skin rashes that started when he was 4. We had skin patch testing done. He’s allergic to hydrocortisone, formaldehyde, fragrance. Once we took gluten out of his diet as well his rashes were more under control. Every time I listen to your podcasts I think some of my son’s issues point back to his MTHFR. Do I take this to his pediatrician? Do I work with his psychiatrist? Do I see a functional medical doctor? What do we do next?

– Mindy J.

ADHD on top of MTHFR is very common and it’s a difficult situation because the medications that help so many other kiddos just don’t work here. I DO think that addressing the MTHFR is the next best step. I would talk with both his psychiatrist and his pediatrician and see if either of them is comfortable fielding this issue in a way other than prescribing massive doses of folic acid, because that won’t be helpful.

If they aren’t familiar enough with MTHFR, then find a practitioner who is. It’s always best to work with someone local, but if you can’t find someone then I do still work with people one-on-one. Check the Amy + Health Coaching link at the top of the page on tohealthwiththat.com

This is why MTHFR folks need other Bs. It isn’t just about folate.

Hi! I am compound heterozygous so I of course have the C/T and A/C copies. I am hoping to start trying to get pregnant soon and I want to know what vitamins I should be taking that will work with the copies that I have. I am on 5mg of l-methylfolafe right now but no B vitamins. I tried a b complex and it made me very mean and hateful so I have been scared to try anything else. I want to have the best chance at a healthy pregnancy, thank you!

– Breonna H.

Congratulations on future baby-making, Breonna. That is such an exciting time. I’m so glad you brought this up because it’s really common for people to start 5-LMTHF before other B vitamins or B12 and then have weird reactions to other Bs when they start.

It is absolutely crucial that you do start other B vitamins. I think the reason why the B complex made you mean and hateful before was that with the other B vitamins there, suddenly your dose of 5-LMTHF was way too high so it was actually that causing the mood and attitude changes and not the Bs.

Basically what is happening in this situation is that your MTHFR enzyme is still really limited because it needs other B vitamins to work – riboflavin is a direct cofactor and without riboflavin, it just won’t go. So your dietary intake of riboflavin was maxing out the amount of 5-LMTHF that you can use.

So you do need to add a B complex back in there, but before you do, drop your 5-LMTHF down to 1mg for a couple of weeks and then add the B-complex. Also, check the B12 in the B complex because some people have a weird reaction to methyl-B12 too. Here’s a post on all the different forms of B12.

When you do give this a try, let me know how it all goes!

How do my folate levels drop after starting Metanx and multivitamin with active folate?

– Human

This is another great question, and I’m actually guessing a bit because I don’t know where your folate levels were before you started. I can say that what I see often in clients is that they come in with super high folate on lab tests, but functional folate deficiencies. Once we eliminate the folic acid and get them started on active folate then blood levels are technically getting lower because we’re clearing out the unmetabolized folic acid that hangs around in there cluttering up the works. Or at least that’s what we hope to do. Even as folate levels look like they’re dropping, the person is symptomatically improving.

I see that happen a lot, but if that doesn’t sound like what is going on for you, reach out again and give me a bit more detail so I can answer more thoroughly. Just remember that serum folate measures everything in the serum – usually that includes natural folate, 5-LMTHF that has been made by your body, whatever folate you’re taking, PLUS any unmetabolized folic acid that is still kicking around. It isn’t a great test on in terms of value on its own, but what we can do is exactly what you’re doing, which is compare numbers over time. But typically we want this to drop a bit as the unmetabolized folic acid (or UMFA) is leaving your system.

I *love* listener questions and I’d love to answer yours. If you happen to have a question, let me know. There is a video-ask for questions on the home page of tohealthwiththat.com. I’ll try to do an answer podcast every month or two just depending on how many questions come in. I also love meeting you guys in Genetic Rockstars, it’s an MTHFR community away from the craziness of social media with lots of inside information, polls, tips, and generally other MTHFR folks who are talking about their experiences. Please join us at community.tohealthwiththat.com.

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