Understanding Pregnancy Loss, Infertility, Birth Defects and the MTHFR gene

What Everyone Should Know

After last week’s post explaining the lack of connection between variations in the MTHFR gene and elevated levels of estrogen or “toxic estrogen,” I received a flood of questions about MTHFR and recurrent pregnancy loss and infertility. Many people also revealed that based on their MTHFR results they were taking “natural folate” instead of folic acid.

Given the interest, I felt it was important to tackle these other other reproductive health conditions and MTHFR, and to also add in a third that frequently comes up—neural tube defects (a birth defect that affects the brain and spine).

MTHFR Primer

The MTHFR gene produces the enzyme methylenetetrahydrofolate reductase, which converts 5,10-methylenetetrahydrofolate to the primary form of folate (5-methyltetrahydrofolate) that is used by the body. This gene touches many functions in our bodies. For a more detailed review on MTHFR, please see the post on MTHFR testing and estrogen.

There are two common spelling changes or variations in the genetic code for the MTHFR gene, known as C677T and A1298C. These genetic variants are also known as “polymorphisms,” meaning they are common in the general population. In fact, 30-40% of people will have at least one copy of the C677T or A1298C polymorphism (variant), while some have a polymorphism on both copies of the MTHFR gene.

Many people have erroneously linked MTHFR polymorphisms with a myriad of medical conditions. In the world of reproductive medicine, it is blamed for a host of things, such as infertility, miscarriages, stillbirths, failure of in vitro fertilization (IVF), preecplampsia (a serious medical condition during pregnancy), and having a child with autism, Down syndrome, birth defects that impact the heart (congenital heart disease), and neural tube defects.

I’ve had infertility, a pregnancy loss, and a child with a serious congenital heart defect. The infertility therapy resulted in a very complicated triplet pregnancy. I delivered extremely prematurely. One son died at birth and one had a serious birth defect affecting his heart—so grave that he needed surgery as soon as possible, but he was too small to have it as he only weighed 1 lb 11 ounces (783 g) at birth. He was physically large enough for the equipment when he weighed 2.6 lbs (1,200 g), and so that is when he had his first procedure.

There was no explanation for any of this. No diagnosis for the infertility. No reason other than triplets to delivery so catastrophically early. No reason Oliver had two serious structural problems with his heart. I get the lure of wanting a unifying diagnosis to explain everything that went wrong in a pregnancy, I really do. Most of us prefer simple answers, but in addition, not knowing why something happened can be frightening and disempowering. It leaves the door wide open to, What Next? It can feel as if you are walking around with the oppressive storm cloud of another medical catastrophe looming overhead just waiting to burst. It’s hard to even begin to heal from a trauma and move forward without an explanation. How do you reframe something when you don’t know it in its entirety? And then there is planning another pregnancy. When something went terribly wrong the first time, the desire to do anything to prevent that from happening again is truly visceral.

Sometimes the science can explain the seemingly unexplainable, but often it hasn’t caught up with everything we need to know, and that is hard. It is important to know that MTHFR testing is not that seemingly undiscovered science that can explain infertility, pregnancy loss, or birth defects. Here’s why.

Infertility, Recurrent Miscarriage, Stillbirth, and MTHFR

There appear to be two main hypotheses concerning MTHFR polymorphisms (or variants) C677T and A1298C and recurrent miscarriage or still birth. One, the idea that reduced activity of MTHFR could lead to elevated levels of homocysteine (an amino acid), leading to blood clots in the placenta and consequently miscarriage or stillbirth. The other theory involves a concern about low levels of folate due to the MTHFR variant, as low levels of folate are associated with neural tube defects, which are severe birth defects of the brain and spine. This second theory postulates that some early miscarriages or stillbirths due to a MTHFR variant are fetuses with neural tube defects. As far as infertility is concerned, it seems that most of the discussion surrounds implantation, meaning the hypothesis is the embryo fails to implant or miscarries very soon after implantation either due to high levels of homocysteine or low levels of folate or both.

The A1298C polymorphisms causes no effects in the body, including any negative pregnancy outcome, so this should be considered the equivalent of blue eyes—it is a genetic difference that some people have and is of no medical consequence. Similarly, one copy of the C677T polymorphism has no medical consequences. With that in mind, the rest of our discussion will focus on people with two copies of the C677T polymorphism or variant.

Regarding the blood clot theory, MTHFR polymorphisms are not associated with an increased risk of blood clots during pregnancy (or in nonpregnant women for that matter). So, the concern about the polymorphism affecting placental health via the blood clot mechanism is unfounded.  

However, some individuals who carry two copies of the C677T polymorphism can have slightly higher levels of homocysteine and lower levels of folate: Might there be issues here? 

Let’s look at recurrent miscarriage first. A large meta-analysis, meaning a study that combined data from several other studies, found no link between two copies of the G677T polymorphism (or variant) and recurrent miscarriage, but in this meta-analysis levels of homocysteine weren’t included. Further studies looking at the data by region identified a small increased risk for recurrent pregnancy loss among women of East Asian heritage, but not for other populations. Why might some populations have a slight increased risk? One possibility is nutrition. It can be hard to get enough folate from diet alone. In some countries, such as the United States and Canada, cereals and flour and other foods are fortified with folic acid, a form of folate. Folic acid easily raises folate levels and reduces levels of homocysteine. This fortification might help the body compensate for the minor fluctuations in homocysteine and folate seen in some people with two copies of the C677T polymorphism or variant. 

Some data suggests that individuals with two copies of the GC77T polymorphism and who ALSO have elevated levels of homocysteine may have a mild to moderate increased risk of recurrent miscarriage, but the data is conflicting and a true cause and effect has not been established Currently, no professional medical organization recommends testing for MTHFR or measuring homocysteine levels for recurrent pregnancy loss.

The recommended dose of folic acid in prenatal vitamins, 400 mcg (micrograms) will normalize the homocysteine levels and folate — even for people with one, two, or both copies of the C677T and A1298C MTHFR polymorphisms (variants). Basically, folic acid has you covered. 

What about Neural Tube Defects?

There is a known link between insufficient folate and neural tube defects, and taking a supplement with 400 mcg of folic acid before getting pregnant reduces this risk. Based on this information, it’s reasonable to wonder if this might apply to MTHFR polymorphisms in some way, as MTHFR is involved with folate metabolism.

While some studies have shown a link between two copies of the C677T polymorphism and neural tube defects, other studies suggest otherwise. Further evidence against a link comes by way of data that shows dietary intake of folic acid is far more important in determining levels of folate than a MTHFR variation. It is possible that there is a link between neural tube defects and MTHFR for some women with two copies of the C677T polymorphism, but the magnitude of the effect is low and the most important factor is whether there is adequate dietary folic acid. Again, folic acid has you covered.

The current recommendation is not to order MTHFR testing or to use the results of MTHFR testing to inform for risk related to neural tube defects, but rather to recommend that everyone attempting pregnancy take 400 mcg of folic acid, the one intervention that HAS been shown to reduce neural tube defects (and is much cheaper than an MTHFR test!). Women who have previously had a baby with a neural tube defect should be taking 4 mg of folic acid a day. 

MTHFR Testing Just Isn’t Indicated

The American College of Obstetrics and Gynecology (ACOG), the Association for Reproductive Medicine (ASRM), the American College for Medical Genetics (ACMG), and the National Society of Genetic Counselors (NSGC)— the medical experts in infertility, pregnancy loss, pregnancy complications, and genetic medicine — all recommend against testing for MTHFR polymorphisms for infertility, recurrent miscarriages, and neural tube defects. Simply put, you don’t need the test.

I know it may be shocking or upsetting to read this, especially if you have been told by your provider that testing for MTHFR polymorphisms was important for diagnosing the cause of your infertility or recurrent miscarriages or for explaining a neural tube defect. The truth is, if you were told this you were given bad information. The experts who study genetics and pregnancy complications have no incentive to hide or withhold MTHFR testing from you. The order tons of tests, often very obscure ones that only those in genetics understand. They are all about testing, but that also means only doing a test when the information that may be provided will be useful. The MTHFR gene is perhaps the most studied gene, if testing were important for infertility, recurrent miscarriage, or neural tube defects we’d know by now and experts would recommend testing. What these experts do recommend is 400 mcg of folic acid a day.

What angers me most about providers who order MTHFR testing for pregnancy complications is people with infertility, those who have had recurrent pregnancy losses, and people with a history of having a baby with a neural tube defect (or any serious birth defect) are often desperate. Many have been traumatized and they want answers. They may be frightened about their reproductive future. And infertility therapy is expensive and can be emotionally devastating, so you can understand how someone might want to do every test possible to maximize outcomes. MTHFR testing will not help achieve the goal of having a baby, but taking 400 mcg of folic acid a day before getting pregnant will.

Providers who order MTHFR testing for pregnancy either don’t know the data and aren’t following guidelines, or they are charlatans who know that 30-40% of the tests will come back positive for a polymorphism allowing them to offer “answers” missed by medicine to at least a third of their patients. In this situation, a positive result is often a gateway to more testing and more return visits. For those providers who sell special supplements and meal plans to manage the non-existent issues related to MTHFR polymorphisms, there are even more opportunities to make a sale. These supplements may even have risks. More on that in tomorrow’s post on the difference between folic acid, dietary folates, and so-called “natural food” folate, and why it matters.

I have a list of rules on how to access information online, and #4 is…

If the provider or site recommends MTHFR testing, you’ve found a source of disinformation. Close the browser or get up and walk out the door.  

Making promises about identifying a cause for infertility, recurrent pregnancy loss, or neural tube defects based on MTHFR testing isn’t just medically incorrect, it’s predatory and cruel.

Special thanks to Elizabeth Fieg, MS, CGC for reviewing the science.