Do Elevated Natural Killer Cells Cause Recurrent Miscarriages?

The Fertility Controversy About NK Cells and Miscarriages

A natural killer cell of the innate immune system. The yellow particles inside the cell represents the toxin
Are an elevated level of natural killer cells (NK cells) a cause of recurrent miscarriages?. Getty Images/Stocktrek Images

Whether or not natural killer cells (NK cells) cause miscarriage is a widely debated topic among fertility specialists. What do we know about the presence of NK cells in those with recurrent miscarriages, and what are the risks and benefits of any possible treatments?

What are Natural Killer Cells (NK Cells)?

Natural killer cells (NK cells) are a type of lymphocyte, one of the types of white blood cells in our immune system.

These cells are "fighters," responsible for eliminating viral-infected cells and even cancer cells from our bodies.

What is the Function of Natural Killer Cells in the Immune System?

Our immune systems are broken down into two basic parts. The "innate immune system" or "cell-mediated immune system" works in a non-specific way, attacking anything foreign which enters our bodies regardless of what it is. In contrast, the acquired immune system is the part of the immune system which addresses specific invaders. This part of the immune system is responsible for remembering an invader and being ready if it should be return. As such, it plays an important role in the immunizations you have received against common infections.

As part of the innate (or non-specific) immune system. NK cells have two primary functions:

  • NK cells may bind with an intruder, releasing toxic granules which either explode the cell or cause it to slowly die
  • NK cells may function as immunoregulators, controlling other parts of the immune system through the production of cytokines

What do We Know about Natural Killer Cells (NK Cells) and Miscarriage?

There is a lot of evidence that natural killer cells are elevated in the bloodsteam (and uterus) of women with recurrent miscarriages, but not so much evidence that the NK cells themselves are causing these miscarriages.

Despite the strange sounding name, natural killer cells are not a bad thing to have. NK cells play a vital role in the functioning of the immune system. They help the body fight off tumors and destroy cells that are infected by viruses as well as cancer cells.

Because of elevated NK cells levels in women with recurrent miscarriages, some researchers believe that NK cells may also be responsible for a woman's body terminating a pregnancy. However, there are other reasons why the NK cells could be elevated.

The Case For NK Cells in Miscarriage

It's hard to dispute that NK cells are elevated in women who have recurrent miscarriages since numerous studies have found this to be true. Researchers have even suggested that elevated NK cells could be behind as many as one-third of all unexplained miscarriages.

Scientists have fleshed out a few mechanisms in which elevated NK cells could terminate an otherwise viable pregnancy, usually promoting the idea that a disordered immune system causes the cells to attack the pregnancy. At least one study has found evidence that NK cells in the uterus attack cells from the pregnancy in cases of spontaneous miscarriage, although it's unclear what those results mean.

Some researchers have even looked at the chromosomes of the miscarried pregnancy to determine whether the NK cells were elevated because of the body's natural response to a chromosomally abnormal pregnancy. The researchers discovered that women with elevated NK cells were potentially more likely to miscarry a chromosomally normal baby in their next pregnancy.

If true, elevated NK cells are causing viable pregnancies to miscarry, reducing elevated NK cells should lead to reduced risk of miscarriage. Studies have looked at the use of both corticosteroids (such as prednisolone) and IV immunoglobulins (IV gammaglobulin) for those with a history of recurrent miscarriage.

A few studies have found that these treatments, especially IV immunoglobulins may increase the chance that participants will carry their next pregnancy to term. Researchers recommend that further studies should be done to understand the risks and benefits of these treatments.

The Case Against NK Cells in Miscarriage

There are plenty of alternative explanations for the finding of elevated NK cells in women with recurrent miscarriages.

There is evidence that stress can cause fluctuations in NK cells. A study from 2006 found that women with recurrent miscarriages could have elevated NK cells in a first of two blood draws-–but then in a second blood draw 20 minutes later, they could show no elevation of NK cells as compared to women with no history of miscarriage. The researchers speculated that there was a chance that some women tended to have an immune system that responded more readily to stress, which might tie in with some other research showing correlations between stress and miscarriage.

There is certainly the possibility as well that elevated NK cells to not "cause" an increased risk of miscarriage, but that both elevated NK cells and recurrent miscarriages are related to a common immune condition which can lead to both. One investigation looked at link between NK cells, miscarriage, and mild thyroid disease.

Natural Killer Cell Related Therapies for Miscarriage

There is a lot of research left to be done analyzing the presence of elevated NK cells among those with recurrent miscarriages, and any treatment is still considered experimental at this time. While IV immunoglobulin has recently been linked with a reduction in recurrent miscarriages and given the thumbs up, any of these treatment need to be weighed. Studies have found that high dose corticosteroids may negatively affect early pregnancy. Any treatment which is considered experimental needs to be carefully weighed with regard to both the possible benefits and the risk of treatment.

Despite the occasional headlines, no medical organization formally recommends testing for and treating NK cells in women with recurrent miscarriages. There is a lot more research that needs to be done before anyone can truly recommend steroids or immune suppressants as a recurrent miscarriage treatment. Any treatment for elevated NK cells should be considered experimental at this point. At the same time that these treatments may not be helpful, they all carry side effects which would need to be weighed against any benefits.

Bottom Line on NK Cell Related Therapies with Repeated Miscarriages

There are many gaps in understanding how NK cells affect pregnancy.

If you've been having miscarriage after miscarriage, you may be willing to try just about anything whenever for the chance that it might work. If you are pursuing immune system therapies for elevated NK cells, make sure that you understand the uncertainties in the research and work with a specialist who doesn't ensure unreasonable promises. Make sure that you weigh whatever benefits that are being found against the possible risks of the treatments in early pregnancy.

Coping with recurrent miscarriages is very difficult in so many ways. There are many emotional and physical concerns that those who haven't faced this simply can't understand. You've probably received enough platitudes that you hesitate to answer your phone at times. Thankfully (or sadly) you are not alone. There are now excellent online support communities through which women can connect with others who "have been there" and understand some of the emotions that those who haven't been there can't begin to comprehend.

Sources:

Cohen, B., and S. Machupalli. Use of Gammaglobulin to Lower Elevated Natural Killer Cells in Patients with Recurrent Miscarriage. Journal of Reproductive Medicine. 2015. 60(7-8):294-300.

Kwak-Kim, J., Bao, S., Lee, S., Kim, J., and A. Gilman-Sachs. Immunological Modes of Pregnancy Loss: Inflammation, Immune Effectors, and Stress. American Journal of Reproductive Immunology. 2014. 72():129-40.

Namdar, J., Kayvan, J., Nezafat, F., Abbaspour, A., Ghafoori, G., Ghobadi, Y., and S. Gholizadeh. Pregnancy Outcomes Following the Administration of High Doses of Dexamethasone in Early Pregnancy. Clinical and Experimental Reproductive Medicine. 2016. 43(1):15-25.

Polanski, L., Barbosa, M., Martins, W., Baumgarten, M., Campbell, B., Brosens, J., Quenby, S., and N. Raine-Fenning. Interventions to Improve Reproductive Outcomes in Women with Elevated Natural Killer Cells Undergoing Assisted Reproduction Techniques: A Systematic Review of Literature. Human Reproduction. 2014. 29(1):65-75.,/p>

Seshadri, S., and S. Sunkara. Natural Killer Cells in Female Infertility and Recurrent Miscarriage: A Systematic Review and Meta-Analysis. Human Reproduction Update. 2014. 20(3):429-38.

Triggianese, P., Perricone, C., Conigliro, P., Chimenti, M., Perricone, R., and C. De Carolis. Peripheral Blood Natural Killer Cells and Mild Thyroid Abnormalities in Women with Reproductive Failure. International Journal of Immunopathology and Pharmacology. 2016. 29(1):65-75.

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