Natural Killer Cells and Infertility: What to Know

Natural killer (NK) cells and their possible connection to unexplained infertility, repeated IVF embryo implantation failure, and repeated miscarriage is a hot—but controversial—topic in the fertility world. Here’s what you need to know so you can make informed decisions on natural killer cell testing and treatment.

Types of NK Cells

Despite their negative-sounding name, natural killer cells are not the enemy. They are an essential part of the immune system. Natural killer cells vary depending on where they are in the body and their molecular make-up. Slight molecular variations can make a big difference in how the cells act.

When discussing fertility, there are two kinds of natural killer cells to know and understand: peripheral natural killer cells and uterine natural killer cells.

Peripheral Natural Killer Cells

Natural killer cells that circulate in the bloodstream are known as peripheral natural killer cells, or pNK. These cells glow brightly under an electron microscope due to an abundance of a particular cell antigen (or molecular “attachment” known as C16) and are sometimes called bright natural killer cells. The bright natural killer cells can trigger a cell to self-destruct.

The primary goal of peripheral natural killer cells is to identify foreign invaders that may threaten the body. This includes cells infected with viruses and abnormal or stressed cells, like cancer cells. Recognition and marking of the foreign invader leads to a series of biological events that end in the destruction of the “enemy” cell.

Uterine Natural Killer Cells

The natural killer cells in the uterus function in a different way. Natural killer cells that are found in the uterus are known as uterine natural killer cells, or uNK. They were originally considered a subset of peripheral natural killer cells because they too had a bright appearance under the electron microscope.

However, uterine natural killer cells don’t have the destructive power of the peripheral natural killer cells. Uterine natural killer cells have much fewer of the “bright” C16 attachment, which is what makes a peripheral natural killer cell most lethal. Labeling them “natural killer cells” may have been a mistake.

We don’t completely understand yet what role uterine natural killer cells have, but we know that they play a critical role in the preparation of the endometrium for the embryo. They also seem to play an important role in the development of the placenta in early pregnancy.

The Controversy

Some fertility experts claim that uterine natural killer cells—the most abundant immune cell in the uterus—explain why some people can’t get pregnant, can’t get a positive pregnancy test after a successful embryo transfer, or repeatedly miscarry.

These experts say that there are tests that can show whether abnormally high levels of natural killer cells are a potential issue, and immunological therapies that can improve the odds of a live birth for these frustrated couples.

However, there are other fertility experts who say there is not nearly enough evidence to justify these tests or the suggested treatments. These experts say the science used to explain the role of natural killer cells in infertility is flawed and based on an outdated misunderstanding of their role in reproduction.

Those who are pro-testing and treatment of natural killer cells say it’s unethical to withhold treatment from women and couples who have been struggling to conceive—even if the evidence for that treatment is not particularly strong.

Those who are against natural killer cell testing and treatment say it’s unethical to order diagnostic labs and procedures that are invasive and expensive when they are not yet proven to be useful.

They also say it’s wrong to expose people trying to conceive to immunological therapies—which come with rare but potentially serious risks—when the benefits of those treatments are not apparent.

Arguments for Testing
  • Could explain infertility

  • Identifies cells responsible for miscarriages and the reason why people cannot get positive pregnancy results

  • Withholding treatment is unethical

  • People should be given the option

Arguments Against Testing
  • Information on NKs is outdated

  • NK's role in reproduction is misunderstood

  • Ordering invasive and expensive tests is unethical

  • Treatments expose patients to serious risks

Links to Infertility and Miscarriage

What’s the possible connection between uterine natural killer cells and getting (and maintaining) pregnancy? The quick but truthful answer is we don’t really know (yet). The original theory was that having too many uterine natural killer cells could lead to the immune system rejecting and attacking an embryo.

The uterine NK cells would identify the fetal cells as foreign invaders and mark them for death. This theory was proposed to explain unexplained infertility, recurrent miscarriage, and repeated failed IVF implantation. It was based on the assumption that uterine natural killer cells acted like the ones that circulate in the bloodstream.

Many fertility experts now recognize that this is inaccurate. Uterine natural killer cells do not attack the embryo. They also do not behave the same as the NK cells in the bloodstream.

Uterine natural killer cells never come into direct contact with the fetal cells—they only have direct access to placental cells.

Despite being put into the same immunological class of cells as peripheral natural killer cells, uNKs have different roles and capabilities. Still, this doesn’t mean that uterine natural killer cells may not be a cause of fertility problems.

Uterine NK cells are vital to the development of a healthy endometrium and placenta. We know that uterine NK cells are the primary immune cells present in the uterus. We also know they make up over 30% of the endometrial cells developed during the luteal phase. But whether and how uterine NK cell activity contributes to infertility, IVF failure, and miscarriage is unclear.

NK Cell Testing

Some fertility experts believe that abnormally high levels of NK cells may indicate or be a cause of fertility problems. Natural killer cell testing is not a routine fertility test and not conducted by all fertility clinics.

Those that do order the testing will only do so in cases of unexplained infertility, unexplained recurrent miscarriage, or repeated implantation failure during IVF treatment.

There are two tests that may be done: peripheral natural killer cell testing and uterine natural killer cell testing.

Peripheral NK cell testing is a blood test and seeks to measure the percentage and quantity of NK cells in the bloodstream. Uterine NK cell testing can only be done via an endometrial biopsy.

This may be done along with other tests that justify endometrial biopsy. As with peripheral natural killer cell testing, the idea is to look at the quantity and percentage of uterine natural killer cells present.  

What to expect during an endometrial biopsy
Illustration by Cindy Chung, Verywell 

An endometrial biopsy involves inserting a thin catheter through the cervix and into the uterus. A clamp may be used to steady or dilate the cervix. Once the catheter is placed through the cervix and into the uterus several inches, the doctor moves it around to gently scrape the uterine wall. This is how the sample is collected.

The procedure takes 10 to 15 minute and may cause cramping. Over-the-counter pain medications (like ibuprofen) are recommended. You may experience spotting. There is a rare but potential risk of infection.  

Whether your doctor is testing peripheral or uterine NK cells, there are no established abnormally high NK cell levels, making an evaluation of the results unique to the lab and your fertility doctor’s experience.

Problems With NK Cell Testing

NK cell testing is controversial in the fertility world. There are no firmly established guidelines for what would be considered “abnormally” high NK cell levels for fertility testing purposes.

Even individual research studies on the topic use different ways to indicate a “high” or “normal” NK cell test result. Fertility doctors who believe NK cell testing is beneficial interpret results based on their clinical and professional experience.

The amount of natural killer cells present in the body varies significantly based on multiple factors, which makes evaluating results even more difficult. These include:

  • Cycle day (during the menstrual cycle)
  • Time of day
  • Recent or current illness
  • Overall stress levels
  • Exercise habits
  • Gender
  • Age

Even among those who are in favor of NK cell testing, there is a difference of opinion on whether blood tests for natural killer cells really can tell you anything with regard to fertility.

There’s no known connection between the percentage or quantity of peripheral natural killer cells and uterine natural killer cells.

Lastly, uterine natural killer cell testing—considered the better indicator of problems—requires an invasive procedure. An endometrial biopsy may be done for other fertility testing purposes, of more established fertility problems. But whether it’s worth the risk for natural killer cell testing alone, when it’s questionable whether the test is even beneficial, is a point of controversy.

Possible Treatments

While the treatments for “high” NK cell problems vary, the theme is the same—to suppress the immune system in hopes that this will change uterine NK cell activity. Some reproductive endocrinologists will suggest these treatments after NK cell testing, while others might recommend them based on prior history (for example, if there have been repeated unexplained IVF embryo implantation failures).

Intravenous Immunoglobulins (IVIg)

Intravenous immunoglobulin is sterilized IgG—specialized immune antibody proteins—extracted from blood plasma donations. It’s given intravenously. The primary original use for IVIg is for those with compromised immune systems, but the treatment is also used off-label for a variety of diseases, including suspected immunological fertility problems.

Because IVIg is extracted from blood plasma donations, and there is a shortage of supply, the cost of treatment can be very expensive (a couple thousand dollars per infusion).

In low-risk patients, the side effects are generally mild and short-lasting: Headache, fever, chills, fatigue, nausea, racing heartbeat, and blood pressure variations. There are some extremely rare but potentially serious risks, including acute kidney failure and risk of life-threatening blood clots.

Studies on whether IVIg can improve success rates for women with a history of recurrent miscarriage or repeated IVF implantation failure have been inconsistent. Some studies have found decreased miscarriage rates and improved clinical pregnancy rates for those with a history of repeated IVF failure. Other studies show no significant benefits.

Intralipids

Intralipids are an intravenously delivered nutritional supplement made up of soy and egg fats, glycerin, and water. Usually, intralipids are used to treat patients with disease-related malnutrition.

Some possible side effects of intralipids include headache, dizziness, fatigue, nausea and/or vomiting, and sweating. There is a very rare (less than 1%) risk of having a potentially life-threatening allergic reaction.

When compared to IVIg, some studies have found that intralipids have shown similar improvements in IVF clinic pregnancy rates and decreased miscarriage rates. Intralipids are significantly less expensive than IVIg as well—costing several hundred dollars (for multiple infusions before embryo transfer and after a positive pregnancy test) instead of thousands of dollars, like IVIg.

Like IVIg, whether or not intralipids truly improve IVF success rates and reduce the miscarriage rate is unclear. Whether or not they have any affect on natural killer cell activity is also debatable.

Oral Prednisolone

Prednisolone is a corticosteroid used to treat a wide variety of diseases and illnesses, such as allergic reactions, asthma, arthritis, and other inflammatory conditions. It has been suggested as a potential treatment for recurrent miscarriage and repeated IVF implantation failure.

Oral prednisolone is relatively low risk when taken for short time periods and significantly less expensive than intralipids or IVIg infusions. Some common side effects of prednisolone include an increase in appetite, weight gain, irritability, and developing a round, puffy face.

One of the major concerns with prednisolone is it’s frequently continued for several weeks after conception. Research has found that prednisolone increases the risk of cleft lip and may decrease birth weight in newborn infants. Not all the potential risks to the unborn baby are known.

Some studies have seen improvements in outcomes with prednisolone, while others have not found a benefit.

A Word From Verywell

Every fertility treatment comes with potential risks. This is true for the established treatments and those that are newer. The controversy over natural killer cells and their role in fertility—along with the controversy over whether the treatments are truly beneficial—can make for a confusing experience.

Your doctor’s professional experience and opinion will likely have an impact on whether this testing and/or treatment is suggested for you. Don’t hesitate to get a second opinion. If you decide to try it, remember that this is still considered experimental in some fertility circles. If you decide to forgo this treatment, know that you’re not passing on a miracle cure.

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6 Sources
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