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Natural Killer Cells in Miscarriage and Infertility

There has been much interest in the possible role of the immune system in determining the outcome of fertility treatment and pregnancy. Unfortunately, there has been much misinformation about the role of natural killer cells in miscarriage and infertility. Natural killer cells, also known as NK cells or CD56 cells, have been perhaps misnamed and this contributes to the confusion surrounding them.  Natural killer cells are a diverse group of cells that can be found in the blood and other areas of the body including the uterus. They earned the name “killer” cells because it was found that the type of natural killer cells found to circulate in the blood were able to bind to and kill certain cancer cells and virus infected cells. However, other types of NK cells lack this ability or only to a much lesser extent.

Blood tests for Natural Killer Cells are not helpful

Based on the assumed similarities between NK cells in blood and uterine NK cells, it has become increasingly common for fertility doctors to recommend blood tests for Natural Killer cells in women with infertility and recurrent miscarriage. These recommendations are based on the unproven assumption that women with recurrent miscarriage and infertility have abnormalities in the function of their uterine NK cells and that the measurement of NK cells in the blood can somehow identify those women who suffer from a malfunction of their uterine NK cells.

Both of these assumptions appear to be wrong.

First, measurement of the number of percentage of Natural Killer Cells in the blood do not reflect the number in the uterus. The percentage of NK cells in blood can be affected by many factors including sex, ethnicity, stress, and age, but there is no indication that elevated concentrations are ever harmful. On the other hand, uterine NK cells will see their numbers change based on a woman’s hormone production during her menstrual cycle. The levels are low before ovulation and increase dramatically, day by day, after ovulation.

Second, blood NK cells are quite different from uterine NK cells. They look different under a microscope, the react differently and they function differently. For example, uterine NK cells have very weak activity in killing cancer cells. Recently, studies of large groups of women have failed to find any relationship between the levels of NK cells in the blood and either infertility or miscarriage.

These incorrect assumptions have led doctors to recommend ineffective and sometimes dangerous therapies to women to suppress their NK cells such as prednisolone, intravenous Ig (IVIG), intralipid, and TNF-α–blocking agent. This is based on a idea that there is a correlation between excessive number or activity of NK cells and adverse reproductive outcome. As noted above, high quality studies have not found this to be true.

What do uterine NK cells do?

The function of uterine NK cells is not completely understood. Studying the function of uterine NK cells is complex and difficult. The best evidence currently points to uterine NK cells being an important mediator between the placenta and the uterus. To understand this role, it is important to understand some basics about the placenta, the uterus and how the two interact with each other.NK Cells remodel the uterine spiral arteries

The placenta comes from the fetus – not the mother. It is composed of cells called trophoblast cells which literally invade into the mother’s uterine lining. In the mother’s uterus, there are blood vessels called spiral arteries. In order for a pregnancy to be successful, the trophoblast cells must come close to the mother’s spiral arteries and then cause changes in the arteries to ensure that they receive a good blood supply. This is called arterial remodeling. The likely function of uterine NK cells is to “cooperate” with trophoblast cells to guarantee correct arterial remodeling ensuring the supply line to the growing fetus. The uterine NK cells must recognize that fetal cells are present in the uterus and they must be activated to produce the molecules necessary for correct spiral artery remodeling.

Should you undergo treatment for elevated or abnormal NK cells?

Use of the treatments noted above (prednisolone, intravenous Ig (IVIG), intralipid, and TNF-α–blocking agent) is an attempt to suppress the number of uterine NK cells. This is based on a misunderstanding of the basic science. It is not inhibition of uterine NK cells that is needed, but rather the right degree of activation  that is of importance. These treatment therefore could potentially have serious adverse side effects. Incorrect or insufficient remodeling of the spiral arteries can lead to complications of pregnancy such as pre-eclampsia, fetal growth restriction and stillbirth.

Conclusions

  1. Blood tests for natural killer cells are not an indicator of uterine natural killer cell numbers or function and do not predict miscarriage or infertility.
  2. Tests to determine levels or “activity”of uterine natural killer cells are of no benefit either since the exact way that natural killer cells work is not known.
  3. Treatments to suppress natural killer cells lack any scientific validity and are potentially harmful.