Genetics, inflammatory cytokines, and recurrent miscarriage

Recurrent pregnancy loss, or recurrent miscarriage, is defined in research as three or more consecutive pregnancy losses before 20 weeks. This is a heartbreaking reality for up to 3% of couples trying to conceive.

There are many reasons for miscarriages, of course. Genetic studies point towards the importance of inflammation, clotting factors, hormonal regulation, immune response, and detoxification genes. Non-maternal reasons would include chromosomal abnormalities or deleterious mutations that are incompatible with life in the fetus.

This article focuses on the role of inflammation and how it impacts pregnancy. We will dive into several different inflammatory cytokines and look at the genetic variants that increase or decrease the risk of recurrent miscarriage.

I know that recurrent miscarriage is a painful and touchy subject for many women. The goal of this article is simply to explain why it is important to keep inflammation low for some women due to genetic variants. You can find targeted lifestyle and dietary solutions at the end of the article. I want to make it clear, though, that a heightened level of proinflammatory cytokines is only one aspect of recurrent miscarriage. Think of this as one tool in your toolbox.

Balancing inflammatory cytokines in pregnancy

Pregnancy is a delicate balancing act of the immune system. A foreign body with foreign DNA has to grow and thrive – without triggering the innate immune response against foreign DNA. This is called ‘maternal tolerance’ to fetal tissue.[ref]

At the same time, the mother’s immune system still needs to maintain a level of immune response that can fight off potential infections, for both herself and the baby.[ref]

The timing is also important in the immune response. Early in pregnancy, pro-inflammatory cytokines are needed for stimulating the production of more blood vessels in the uterus. As pregnancy proceeds, though, there is a change to less of the pro-inflammatory response and more of the anti-inflammatory response.[ref]

There is a balancing act within the T cells of the immune system. T helper cells are the part of the immune system that can quickly help to ramp up an inflammatory response. There are three main types of T helper cells known as T helper 1 (Th 1), T helper 2 (Th 1), and T helper 17 (Th 17).

Th 1, Th 2, and Th 17 cells all have a role in how the body responds to pathogens as well as to proteins that need to be tolerated in the body. A balance between Th 1 and Th 2 is necessary for the embryo to implant successfully and pregnancy to be maintained.[ref]

Th 2 produces both inflammatory and anti-inflammatory cytokines. Important here is that Th 2 produces IL-10 which is the body’s main way of tamping down the inflammatory response. IL-10 protects the interface between the fetus and the mother by reducing the inflammatory cytokines produced by Th 1.[ref]

The ‘players’ that we will discuss here include:

  • Interleukin 17 (IL-17)
  • Interleukin 1 beta (IL-1B)
  • TNF-alpha
  • Interleukin 10 (IL-10)

IL-17s role in recurrent miscarriages:

Interleukin 17 (IL-17) is a proinflammatory cytokine produce by T helper 17 (Th 17) cells. T helper cells are part of the adaptive immune system, activated by pathogens, and important in fighting off invaders.

IL-17 promotes inflammation through binding to the IL-17 receptor and signaling for immune cells to come to the site of the inflammation. This is great when fighting a nasty virus or bacteria, but the overactivation of IL-17 has links to autoimmune diseases, asthma, and recurrent miscarriages.

Many studies have shown an increase in Th17 and IL-17 in pregnancy complications such as miscarriage, preterm birth, and preeclampsia.[ref][ref] Learn more about Interleukin-17 (IL-17A gene).

Studies on IL-17 and recurrent miscarriage:

  • A study of 120 Egyptian women with recurrent pregnancy loss (RPL) showed higher serum IL-17A levels. Additionally, a genetic variant in IL-17A that increased levels was associated with an increased relative risk of RPL. On the other hand, an IL-17A variant that decreased levels was associated with a decreased relative risk of RPL.[ref]
  • In women with idiopathic recurrent pregnancy loss (RPL), the number of Th-17 cells that produce IL-17 is increased compared to women without RPL.[ref]
  • Another study of women with unexplained RPL showed higher levels of the inflammatory IL-17, IL-23, and IL-6, along with lower levels of the anti-inflammatory IL-10.[ref]

Balancing act: T regulatory cells play an important role in balancing out the IL-17 produced by Th17 cells. One of the ways the body regulates Th17 is through transforming growth factor-β (TGF-β).[ref] Another important factor in balancing out the proinflammatory response is IL-10, an anti-inflammatory cytokine.[ref]

Studies on recurrent pregnancy loss show that the problem could lie in the combination of higher inflammatory cytokines (IL-17, IL-23, and IL-6) along with a lack of balancing T regulatory cells (low TGF-β).[ref]

Other studies point to the decrease in TGF-β from lower numbers of Treg cells as the problem. The lower Treg to Th17 ratio causes an imbalance in inflammatory cytokines.[ref]

Not all studies agree! Some researchers think IL17 may have a modulatory effect in pregnancy maintenance, and some studies show IL-17 genetic variants are not associated with RPL.[ref][ref][ref] Part of the difference may be due to different population groups that are being studied.

Environmental factors common to a geographic region: A recent study of an IL-17 variant shows it may interact with toxoplasmosis (parasite from cat poop) in the risk of recurrent pregnancy loss.[ref] This could explain some of the differences in the studies on Il-17 variants in RPL. Toxoplasmosis is much more common in certain regions. Th17 cells and IL-17 are important in how the body reacts to and fights off the T. gondii parasite that causes toxoplasmosis.[ref]

IL-17A gene variants linked to miscarriage:

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Check your genetic data for rs2275913 (23andMe v4, v5; AncestryDNA):

  • A/A: increased relative risk of recurrent miscarriage[ref][ref]
  • A/G: increased relative risk of recurrent miscarriage
  • G/G: typical

Members: Your genotype for rs2275913 is .

Check your genetic data for rs763780 (23andMe v5; AncestryDNA):

  • C/C: increased relative risk of recurrent miscarriages (Iranian women)[ref]
  • C/T: typical risk
  • T/T: typical risk

Members: Your genotype for rs763780 is .


IL1B and recurrent miscarriages:

Interleukin 1 beta (IL-1B) is a proinflammatory cytokine that increases the expression of IL-17. Genetic mutations that increase the production of IL-1B have links to several autoinflammatory diseases including CAPS (Cryopyrin-associated periodic fever syndrome). (More about CAPS here)

IL-IB plays an important role in stimulating the production of Th 17 cells. Thus, an excess of IL-1B can increase the production of IL-17 via Th 17 cells.

IL1B gene variants linked to miscarriage:

Check your genetic data for rs1143634 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased relative risk of recurrent miscarriages[ref]
  • A/G: typical risk
  • G/G: typical risk

Members: Your genotype for rs1143634 is .

Check your genetic data for rs16944 -511T>C (23andMe v4, v5; AncestryDNA):

  • A/A: typical risk
  • A/G: increased risk of early pregnancy loss[ref]
  • G/G: increased risk of early pregnancy loss[ref][ref]

Members: Your genotype for rs16944 is .


TNF-alpha in pregnancy:

TNF-alpha (tumor necrosis factor-alpha) is an important Th1 inflammatory cytokine. As its name indicates, it is important in controlling the growth of cancer cells. Additionally, TNF-alpha influences cell differentiation of normal cells and also plays a role in many inflammatory diseases. Learn about TNF (Tumor necrosis factor) and how it acts as a signaling molecule in our immune system.

Cell differentiation and cell growth are essential for pregnancy and the growth of the baby. The right level of TNF-alpha is essential here.

In women with recurrent miscarriages, researchers find higher TNF-alpha levels than in women without miscarriages.[ref]

Interestingly, a recent clinical trial showed that anti-TNF alpha medications decreased the risk of miscarriage in women with RPL.[ref]

TNF-alpha genetic variants linked to miscarriages:

Check your genetic data for rs1800629 (23andMe v4, v5; AncestryDNA):

  • A/A: higher TNF-alpha; increased relative risk of recurrent miscarriages[ref]
  • A/G: higher TNF-alpha; slightly increased relative risk of recurrent miscarriages
  • G/G: typical

Members: Your genotype for rs1800629 is .


Balancing out the inflammatory response: IL-10

IL-10 is a cytokine produced by Th 2 cells to balance out the immune response from Th 1 cells.

In pregnancy, IL-10 plays a vital role in maternal tolerance – keeping the immune response to the baby in check.

IL-10 mainly exerts an anti-inflammatory effect in pregnancy, but it also helps to protect against vascular dysfunction. A deficiency of IL-10 in pregnancy can lead to miscarriage, preterm birth, or preeclampsia.[ref]

The more common IL-10 genetic variants have different population frequencies in Asian populations compared to Caucasian, Arab, and African populations. Thus, the research studies on these variants can be population-specific.

IL-10 genetic variants linked to miscarriage:

Check your genetic data for rs1800871 -819C>T (23andMe v4, v5; AncestryDNA):

  • A/A: typical risk in Asians, increased risk of recurrent miscarriages in Caucasians[ref]
  • A/G: decreased relative risk of recurrent miscarriages in Asian populations (not in Caucasian or Arabs)
  • G/G: significantly decreased relative risk of recurrent miscarriages in Asian populations (not in Caucasian or Arabs)[ref]

Members: Your genotype for rs1800871 is .

Check your genetic data for rs1800896 -1082G>A (23andMe v4, v5; AncestryDNA):

  • T/T: typical risk
  • C/T: typical risk
  • C/C: increased relative risk of recurrent miscarriage (Caucasian population group)[ref]

Members: Your genotype for rs1800896 is .


Lifehacks:

Before taking any supplements or making changes, please talk with your doctor or fertility specialist. Pregnancy is not the time to experiment with new drugs or supplements without knowing the effects on the baby.

Vitamin D plays an immunomodulatory role in the body. This means it helps the immune system to function well, but at the same time, keeps it from going overboard. In women with recurrent pregnancy loss, interleukin 17 levels were high and vitamin D levels were significantly decreased.[ref] Other research shows that Vitamin D may decrease or modulate high IL-17 levels.ref]ref]

Testing is your best bet for knowing your vitamin D status. You can order your own tests online through places like Ulta Lab Tests, or you can ask your doctor to include vitamin D testing at your next checkup.

Getting outside in the full sun each day is a great way to increase your vitamin D levels naturally. If your levels are low and you decide to supplement, be sure to read the ingredients on the supplement label. With this in mind, some vitamin D supplements include soybean or cottonseed oil, but others are available with coconut oil. Discover more on the importance of vitamin D here.

Role of the gut microbiome: Researchers investigate the role of the gut microbiome in miscarriage patients. The study showed that IL-17, TNF-alpha, IL-2, and interferon-gamma were increased in the women who had miscarriages. Additionally, there was a shifted microbiome towards microbes that are associated with higher Th 17 and Th 1 levels. Learn more about why the genetic variants you inherited from mom and dad influence the bacteria that reside within you and how dietary changes can make a difference.

For women with gut issues, you may want to consider taking probiotics. Talk with your doctor for recommendations. A meta-analysis of 27 randomized trials of probiotics in pregnancy showed that they neither increased nor decreased the risk of preterm birth.[ref]

Other ways of modulating the gut microbiome include cutting out processed foods and fast food and replacing them with whole foods including fiber-rich fruits and vegetables.

Probiotics containing Bifidobacteria or Lactobacillus may decrease TNF-alpha levels.[ref] One study showed that B. adolescentis decreased TNF-alpha levels and had an antidepressant effect.[ref] Lactobacillus Plantarum restores tight junctions (decrease leaky gut) in the intestines. It also decreased TNF-alpha.[ref][ref]

Anti-inflammatory diet: Including polyphenols, such as the flavonoids found in fruits, vegetables, legumes, and cocoa, in your diet can have an anti-inflammatory effect.[ref]

As important as including fresh fruits and vegetables, though, is cutting out foods that can increase inflammation. Ultra-processed foods, such as packaged snack foods, pizza, candy, pastries, etc., are linked to many negative health outcomes. Ultra-processed foods now make up about 50% of calories in high-income countries. A diet high in ultra-processed foods has links to an increase in risk for irritable bowel syndrome, type-2 diabetes, depression, cancer, and cardiovascular diseases.[ref]

Moderate exercise: If you need a good reason to get out for a long walk (in the sunshine for the vitamin D), exercise is linked to increasing IL-10 and then subsequently reducing IL-1B.[ref] Additionally, exercise has shown to reduce TNF-alpha.[ref]

Zinc is important in immune health, and it has shown to suppress the production of IL-17 in some situations.[ref] Foods high in zinc include oysters, beef, crab, lobster, pork, baked beans, pumpkin seeds, and fortified cereal.[ref]  Learn why zinc is important for your immune system here and so much more.

Glycine has shown to reduce TNF-alpha and inflammation.[ref] Glycine is an amino acid that is abundant in bone broth, collagen, and gelatin.

Magnesium: Low magnesium levels may play a role in higher TNF-alpha levels. Magnesium sulfate, in conjunction with thyroid medication, in hypothyroid rats, decreased TNF-alpha levels.[ref][ref]


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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 from Colorado School of Mines. 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.