Natural Killer (NK) cell testing

What is Natural Killer (NK) cell testing ?

• Natural killer (NK) cells are a type of immune cell found throughout the body, including in the blood and the lining of the uterus (called the endometrium).
• NK cells play an important role in the immune system by helping the body respond to infections and abnormal cells. During an infection, NK cells levels increase to fight the infection. Once the infection is cleared NK cells levels return to a normal range.
• In the uterus, they also play a role in embryo implantation and early pregnancy.
• In IVF, NK cell testing aims to measure both the number of NK cells (how many are present) and/or their activity (how strongly and in what manner they respond).
• Testing can be done using a blood test, which measures NK cells in the bloodstream (sometimes called peripheral NK cells or pNK cells), or an endometrial biopsy, where a small sample from the lining of the uterus is taken to measure NK cells in the uterus (sometimes called uterine NK cells or uNK cells).
• If NK cell testing is done, it is usually done leading up to or during an IVF cycle or embryo transfer.

Why might it improve IVF outcomes?

• The immune system in the uterus plays an important role in embryo implantation and pregnancy. NK cells are part of this immune system.
• It has been suggested that having higher-than-usual levels or activity of NK cells could interfere with the process of implantation, and cause implantation failure or miscarriage. However, this has not been proven as the results of scientific studies have been mixed.
• If NK cell levels or activity are reported as “high”, the IVF specialist might recommend some options that are thought to calm the immune system, such as steroids or intralipid infusions.

Why might it not improve IVF outcomes?

• Most patients probably have normal activity or levels of NK cells.
• It is unclear whether differences in NK cell levels or activity affect the chance of pregnancy. NK cells help with embryo implantation, so having enough of them is important. Some research suggests that people with an "overactive" or "underactive" immune system in the uterus have the same chance of getting pregnant as those with normal immune activity.
• If NK cell levels are measured by a blood test, this measures their level or activity in the bloodstream. This may not reflect what is happening in the uterus, where implantation occurs.
• It’s not been proven whether a blood test or an endometrial biopsy can reliably detect abnormal levels of NK cells. These tests haven’t been validated, and there is no clear agreement on what is considered a “normal,” “high,” or “low” NK cell level or activity.
• NK cell levels can vary naturally between individuals and over time. A single test result may not reflect a person’s typical immune status.
• It is important to remember that implantation failure and miscarriage are common. Most of the time when embryos fail to implant or are miscarried it is due to genetic or chromosomal problems in the embryo itself, rather than issues with the endometrial lining.

Who might consider it?

People who have experienced:

• Recurrent implantation failure
• Recurrent pregnancy loss (recurrent miscarriage)

Learn more about common IVF issues and challenges

Does it work? What the evidence says

There is no randomised controlled trial evidence that assesses the safety or effectiveness of NK cell testing. This means we don’t know whether NK cell testing increases the chance of getting pregnant and having a baby from IVF.

Side effects of NK cell testing

NK cell testing can be performed by blood test via a vein in your arm, or a biopsy of the endometrium which is the lining of the uterus.

Blood test

Aside from minor discomfort or bruising at the blood collection site, side effects are not usually expected for the NK cell blood test.

Endometrial biopsy

If the NK cell test is performed using an endometrial biopsy, this is associated with some pain and side-effects, as described below.

Is endometrial biopsy painful?

The most common side effect of endometrial biopsy is pain - studies report pain scores of around 4 out of 10.

Other side effects of endometrial biopsy

The endometrial biopsy procedure is considered safe and serious complications are rare.

Rare side effects include:

• Prolonged bleeding
• Infection
• Uterine perforation (making a hole in the wall of the uterus) but this is extremely rare
• Feeling faint for a short time during and after the procedure
• Endometrial adhesions, especially if infection occurs, which may require further treatment and could make it more difficult to get pregnant. However, this is very rare.

All medical procedures carry some risk.

In some cases, the endometrial biopsy may be undertaken as part of a surgical procedure, such as a hysteroscopy, which has its own, separate risks. A hysteroscopy is a surgical procedure where an instrument is inserted through the vagina and cervix so the doctor can look inside the uterus. This may be performed under a general anaesthetic.

Risks of NK cell testing and long-term outcomes

There are no known risks or long-term harms.

• This is based on data from randomised controlled trials (of endometrial biopsy) and input from IVF specialists. Possible risks of harm and long-term outcomes are often not reported in randomised trials and therefore it is unknown whether endometrial biopsy poses any risk of harm to the IVF patient or the embryo/baby

An IVF specialist might recommend medication or another treatment based on the test result. These are associated with their own possible risks. Information about intralipid infusions and corticosteroids are available on this website.

NK cell testing has been used in Australia since 2006, and approximately 10,000-15,000 IVF patients have had NK cell testing.

Cost of NK cell testing

NK cell testing usually costs between $150-500  AUD for a blood test or $500-800 AUD for an endometrial biopsy. This indicative cost is per IVF cycle and multiple tests may be recommended. Depending on your test results, there may be additional treatment costs.

Cost information is indicative only, costs can vary from clinic to clinic and depending on different circumstances.

Practical considerations

If NK cell testing is done, it is usually done before an embryo transfer and doesn’t usually need to be done every cycle but your doctor may order multiple test to monitor NK cell levels.

If an endometrial biopsy is performed for the NK cell test, the below information about the procedure is relevant.

• Endometrial biopsy is similar to a smear test, but tends to be more uncomfortable. First, a speculum is placed inside the vagina. Then a thin plastic catheter, usually a pipelle, is inserted through the cervix and into the uterus. The catheter is gently moved back and forth and rotated around, in multiple areas, and a sample of the endometrium is collected at the same time. The catheter is then removed and discarded. The procedure can usually be performed without any anaesthetic and takes approximately 5 minutes. The procedure may require an additional visit to the IVF clinic. If the procedure is undertaken as part of hysteroscopy procedure, it may require a hospital admission.
• Sometimes the procedure is difficult for the clinician to perform, and it may be necessary to use additional techniques such as a tenaculum. In about 3% of people the procedure may not be possible.

Unsure about some of the terms we have used? Use our glossary to understand scientific or unfamiliar terms.