Dads matter: MTHFR variants in fathers affect miscarriage risk

Dealing with the heartbreak of a lost pregnancy can leave many people asking – why?  While the answers aren’t always known, there are some cases where the parents’ genetic variants can interact with diet and lifestyle to increase miscarriage risk.  This article dives into the MTHFR variants and miscarriage risk – with added information

MTHFR and Miscarriages:

There are quite a few studies showing that women carrying certain MTHFR variant combinations are at a somewhat higher risk for recurrent miscarriages. Almost all of these studies point to a small, yet statistically significant increase in miscarriage risk for women carrying MTHFR variants.[ref][ref]

(Want to learn the basics of MTHFR? Check out this article…)

Recently, I ran across a study that added a new twist to the topic.  It turns out that the father’s MTHFR variants can also play a role in recurrent miscarriages.

This makes sense. Both the DNA in the egg and the DNA in the sperm need to be complete and without significant errors in order to become a baby.

Importance of Dad’s MTHFR Variants in miscarriage:

The study from 2015 looked at 225 couples with more than three consecutive pregnancy losses compared with 100 control couples with successful pregnancies.  All 225 mothers in the pregnancy loss group carried either compound heterozygous MTHFR C677T and A1298C variants or homozygous C677T or homozygous A1298C. The study defined carrying just one copy (heterozygous) of either C677T or A1298C as being at low risk for miscarriage.

When the researchers looked at the father’s MTHFR variants, they found that in the pregnancy loss group the men were more likely to carry the risk variants.[ref] This backs up the work of other, smaller studies that also found that the male’s MTHFR status combined with the mother’s MTHFR variants does seem to statistically increase the risk of miscarriage.[ref]

There are a couple of things that could be going on here:

First, fathers who carry the MTHFR variants are likely passing them on to the baby.  There are a couple of studies showing that the baby’s MTHFR variants may play a role in miscarriages. On the other hand, there are quite a few studies studies showing no effect from the baby’s MTHFR gene. Overall, the meta-analyses that combine all the study data tend to show little to no effect from the baby’s MTHFR status, so this is probably not the reason.[ref]

The second possibility of why the father’s MTHFR variants matter could tie in with the fact that men carrying homozygous MTHFR variants are also at a higher overall risk for infertility.

A meta-analysis pooled the results of 20+ studies and showed that men carrying either the homozygous MTHFR C677T or A1298C variants were at a higher risk for infertility (29 – 63% increase).  Statistics here…  Keep in mind that this is just the increase in the risk of infertility compared to the normal risk. For example, if the risk of male infertility is 1 in 20, a 69% increase would make the risk 1.69 in 20.[ref]

One of the final steps in sperm creation involves methylation of the DNA and packing it up correctly in the nucleus. Decreased methylation cycle nutrients could be affecting this final step in sperm creation. Alternatively, the methylation cycle and the MTHFR variants impact the way the cells deal with oxidative stress.  Excessive oxidative stress can also impact and damage the DNA in the sperm. [ref]


Genetic Variants for MTHFR:

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Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical *
  • A/G: one copy of MTHFR C677T allele (heterozygous), decreased by 40%
  • A/A: two copies of MTHFR C677T (homozygous), decreased by 70 – 80%

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: typical *
  • G/T: one copy of MTHFR A1298C (heterozygous), slightly decreased enzyme function
  • G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20%

Members: Your genotype for rs1801131 is .


Lifehacks:

Dads matter!

In conception, pregnancy, and throughout life! It is easy to see how prospective moms need to clean up their diets, exercise, and sleep well before getting pregnant, but I think these studies are a good reminder that prospective fathers need to pay attention to their own health as well!

Eating more folate: 

MTHFR variants (read more here) increase the need for ensuring adequate folate consumption. This means leafy green veggies, legumes, and other organic food sources of folate need to be eaten daily.

Supplemental methyl folate:

If dietary changes aren’t possible, there are methyl folate supplements as well. A quality B12 is also important, and many people find it convenient to take a B-complex to cover all the bases.  Here is one that I like: Jarrow B-Right. But you may find other options that are a better fit for you.

I didn’t find any specific studies looking at men supplementing with folate for recurrent miscarriage, but there are studies showing that it is effective for women. One recent (small) study found that 5mg of methyl folate along with B6 and B12 decreased the risk of miscarriage.[ref]

Folic acid vs. methyl folate:

Please note that methyl folate is likely the better form of supplemental folate vs. folic acid,[ref]  but that some studies show that a folate-rich diet is as effective as either methyl folate or folic acid. [ref]

One reason for methyl folate instead of folic acid is that there have been several recent studies linking high doses of folic acid to things like an increased risk of allergies[ ref] and some epigenetic changes that are a bit of an unknown.[ref]

There are also genetic variants that can impact whether folic acid or methyl folate may work better for you.


Related Genes and Topics:

Genetic links to infertility for women
The statistics on infertility are astounding. The CDC estimates that 12% of women overall in the US have impaired fertility. For women over age 30, that statistic rises to 25%! [ref][ref] Your genes may be playing a role in your infertility — and knowing which genetic variants you carry may help you figure out solutions to try.

Your need for riboflavin (B2): MTHFR and other genetic variants
Riboflavin (Vitamin B2) is a water-soluble vitamin that is a cofactor for many enzymes in the body.  To put it in simpler terms: riboflavin is vitally important!



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.