MTHFR, Fertility, and Pregnancy

MTHFR and fertility and MTHFR and pregnancy are incredibly big topics because MTHFR does change risk parameters for both women and men. Of course, balancing methylation is key for this process, but there are special considerations for preconception, healthy pregnancy, and getting successfully to baby-in-arms.

MTHFR and Sperm Parameters

MTHFR polymorphisms are well know to affect men’s fertility including sperm count and morphology.  Research published in the Journal of Assisted Reproduction and Genetics suggests that the DNA structure of the sperm is altered due to defective methylation, which may explain the hypo-fertility.  The same study also suggests 5-LMTHF as the appropriate treatment, which is kind of wonderful because most of the studies on women’s infertility associated with MTHFR are still beating the folic acid dead horse.

Just like with women, high dose folic acid is a standard medical treatment for improving sperm perameters in men struggling with infertility, but like with women, this may not be the best course of action for men with the MTHFR polymorphism.

One study also shows that for men with MTHFR C677T polymorphisms, high dose folic acid actually decreases DNA methylation in sperm, which is the opposite effect that we’re looiking for in terms of improving fertility. This may be similar to the folic-acid induced “pseudo-MTHFR” that we’ve talked about in previous posts, but essentially it boils down to folic acid actually making things worse rather than better for people with MTHFR mutations.

MTHFR and Repeat Pregnancy Loss

This is an interesting situation where many women with MTHFR experience what is known as “idiopathic” repeat pregnancy loss – idiopathic meaning that nobody knows the cause, but researchers are having a really hard time nailing down what is actually happening.  So one study of genetic variances showed a weak, but not significant enough to be considered conclusive association between MTHFR and Idiopathic recurrent pregnancy loss (or IRCPL).  

Other research specifically study IRPL in women with MTHFR to see if lowering homocysteine or boosting B vitamins will change things for the better. This study showed that 5 mg methylfolate, 50 mg vitamin B6 and 1 mg per week of vitamin B12 decreased homocysteine levels and caused 7 live births in one year out of 16 women who had suffered 3 miscarriages in a row. This is a highly significant improvement.

So the bottom line here is that we know repeat pregnancy loss is happening in women with MTHFR, but it looks more complicated than just having the SNP or not. It is very possible that it comes down to having MTHFR in addition some other related factor like microclotting, high homocysteine, or something unknown.

MTHFR and Clotting in Pregnancy

Increased risk of blood clotting is a known risk for people with MTHFR polymorphsims, but how does that affect women with MTHFR who are trying to get pregnant? Research is showing that MTHFR related micro-clotting could be a risk factor for a number of different pregnancy outcomes.

There are a few really lovely studies showing that repeat pregnancy loss for women with MTHFR mutations might be related to microclotting.  One study, published in the Journal of International Medical Research compared pregnancy outcomes in women with MTHFR C67T polymorphisms, that could be heterozygous or homozygous  between two different clotting protocols.

Group 1 had 81 mg baby aspirin + 5 mg folic acid – note that for reasons we’ve discussed before from other studies, I personally would choose methylfolate over folic acid, but folic acid is the standard of care and that was what was used in this study.

Group 2 had 81 mg baby aspirin + 5 mg folic acid + 0.4 mg per day lovanox, which is an anticoagulant.

Group 3 was a control group, which is used for normal comparison and they were women without MTHFR polymorphisms who were receiving pregnancy and prenatal care in the same clinic at the same time as the other women. 

Group	Delivery Rate	First Trimester Miscarriages	Preeclampsia or Growth Restriction	Intrauterine Fetal Death
1. Aspirin and folic acid	46.3	51%	4.9%	2.4%
2. Aspirin, folic acid, and lovanox	79.7	20.3%	2.4%	0
3. Control	86.3	12.8%	2.6%	0.9%

These results strongly suggest that micro-clotting is a strong contributor to pregnancy loss and other pregnancy complications in women with MTHFR mutations. The study could have been improved if the control group also had MTHFR but was not given anticoagulant therapy. I assume it wasn’t done this way because ethically that could be considered withholding treatment.

High Homocysteine Levels in Pregnancy

High homocysteine levels are a well-documented risk with MTHFR mutations, and it can affect MTHFR and fertility as well. We’ve talked about homocysteine extensively in seasons one and two of the podcast in non-pregnant situations. But high homocysteine in pregnancy brings different complications.  

In a typical pregnancy, homocysteine levels decrease during the pregnancy, reaching their lowest point in the second trimester, then slowly increasing again. They do not return to pre-pregnancy levels until after delivery.

Normal levels of homocysteine during a pregnancy are:

3.9-7.3 mmol/L before 16 weeks gestation

3.5-5.3 mmol/L between 20 and 24 weeks

3.3 – 7.5 mmol/L after 36 weeks.

High homocysteine increases the free radicals, which can injure the cells lining blood vessels in both the mother and the placenta. It can also decrease the blood vessels and circulation overall in the placenta and ultimately lead to complications for the mother and fetus. Also, high homocysteine promotes clotting which can lead to problems in placental circulation withing the pregnancy and in delivery. This is an important metric to track for pregnant women with the MTHFR polymorphism, but unless you are working with a specialist, it is often overlooked.

“HHct [hyperhomocysteinemia, or high blood homocysteine] is conducive to the production of hydrogen peroxide and superoxide free radicals. These adversities will lead to oxidative injuring of endothelial cells [31], diminished blood vessels in villi, and lower blood circulation at the maternal-fetal interface and ultimately lead to poor maternal and neonatal endings. Additionally, HHct promotes cell apoptosis, which induces trophoblast dysfunction [32]. HHct reduces NO released by endothelial cells, and it induces platelet accumulation and promotes thrombosis [33], which in turn affects placental perfusion”

Dai C, Fei Y, Li J, Shi Y, Yang X. A Novel Review of Homocysteine and Pregnancy Complications. Biomed Res Int. 2021 May 6;2021:6652231. doi: 10.1155/2021/6652231. PMID: 34036101; PMCID: PMC8121575.

According to recent studies, HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL) [34–39], preeclampsia (PE) [40, 41], preterm delivery [42, 43], placental abruption [3, 44, 45], fetal growth restriction (FGR) [46–48], and gestational diabetes mellitus (GDM). These are, of course, risks that we’ve talked about with MTHFR.

Getting Pregnant with MTHFR

Obviously, MTHFR and fertility is a big topic and MTHFR brings its own complications for men and women trying to conceive and carry a healthy baby. There are so many factors that go into this, but the most important one is the nutritional preparation that goes into the 6 months before a couple starts trying to conceive. This allows four months for an entirely new, healthy batch of sperm to be cultivated and also gives the woman approximately six cycles to help balance hormones, ensure proper B vitamin levels, make sure her iron levels, thyroid, and other associated risk factors are as good as they can be, and to be ready for a healthy pregnancy.