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Natural Killer Cells & Fertility: Cutting Through the Controversy


A successful IVF cycle is dependent on three main factors: First, the “competency” of an embryo, second, the receptivity of the uterine lining and third the complex interplay between an embryo and the uterus. Lack of success with an IVF cycle is primarily the result of an abnormal, or chromosomally “incompetent,” embryo. That being said, evaluation of other factors, specifically the embryo-uterus interface, cannot be ignored.

One overlooked factor that impacts the interaction between embryo and uterus is the role of the immune system. The immune system within our bodies – and specifically the uterus – works in a mysterious and magnificent way. Just imagine how amazingly complex the intrauterine immune environment is – for a pregnancy to occur, an embryo that is partially derived from another individual (the sperm’s DNA) is allowed to implant within the uterus; however, if a transplanted tissue, or for that matter, a foreign bacteria or virus, enters our bodies, our immune system is swift to attack it and remove/reject it. So how is an embryo that is partially foreign to a woman’s body allowed to implant? This phenomenon has come to be referred to as the “immunologic riddle” of pregnancy. Not only is immunologic acceptance of an embryo essential for pregnancy to occur, but it also sets the scene for our body’s own cells, tissues and organs to be shielded from attack by our own immune systems.

It is well known and accepted that a normal implanting embryo will thrive in a balanced immune environment within the uterus. Within 12-24 hours of reaching the uterus, an embryo will begin the hatching process and begin extending its root system (trophoblast) into the decidua of the lining. One of the main types of immune cells, called lymphocytes, that are in abundance within the lining are commonly referred to as “Natural Killer” cells. These are specialized cells which regulate the ability of an embryo to implant. It is theorized that enhanced activity of these cells (hyperactivation) may contribute to the inability of some embryos to implant — not by “rejecting” an embryo, but by providing a less-ideal environment in which to implant.

This subject is controversial for 3 main reasons:

  1. Not all women with abnormal natural killer cell activity will have a reproductive problem – meaning that some women with abnormal levels may have issues with implantation, others may have recurrent miscarriages, and some may not have any problems whatsoever. That being said, by the time women see a reproductive endocrinologist and infertility specialist, they have already had problems related to pregnancy. That, combined with knowing that the therapy is without any known side effects, leads us towards treating the patient for immune issues.
  2. There is no universally accepted method for assessing natural killer cell activity. Does peripheral blood (a routine blood draw) accurately assess natural killer activity or does a biopsy of the uterus assess it better? That being said, if the peripheral blood shows an abnormality, then it likely will impact the uterus. However, if the blood test is negative, then it is unclear whether the uterus is impacted as well. Assays using uterine biopsies are of questionable accuracy and reliability as there is some overlap between what is considered normal and abnormal, and it is unclear as to when to perform the biopsy within the menstrual cycle (is day 5 better than day 14, etc?).
  3. Until a few years ago, the treatment of choice for abnormal Natural Killer cells was intravenous immunoglobulin (IVIg) which is a substance composed of a pooled specimen of multiple blood donors. This, in theory, increased the risk of communicable disease. It also carried a variety of unpleasant side effects including severe headaches, nausea, lower back pain and tachycardia. And the associated cost was extremely high – several thousand dollars per infusion (with multiple infusions needed). All of these factors made physicians very nervous to use IVIg for the treatment of immune issues, which then fueled the controversy. Imagine being a doctor and recommending a procedure that would cost you $5,000 or more, would have very unpleasant side effects, and may or may not improve your chances of pregnancy! But this has all changed with the introduction a few years ago of a product called IntraLipids that have replaced IVIg as the treatment of choice for activated Natural Killer cells at SIRM. Intralipids are soy based and are not blood products. IntraLipids are routinely used as part of intravenous nutrition provided to premature infants and malnourished adults. The cost for a single infusion is <$400. And there are no known side effects related to IntraLipid infusions – no known cancer risks, birth defects, or developmental issues.

So, the role of the immune system in accepting and providing a healthy environment for a pregnancy is not controversial. This fact is universally accepted. Making a blanket statement that natural killer cell testing is not appropriate for a certain subgroup of individuals is therefore also not appropriate. Studies are beginning to surface that demonstrate IntraLipid therapy does in fact improve the odds of pregnancy for those with recurrent implantation failure. In fact, well-reputed journals (Human Reproduction (2016) 31 (1): 217218; “The absence of evidence is not the evidence of absence” and (2015) 30 (7): 1526-1531 “Enough! Stop the arguments and get on with the science of natural killer cell testing”) are publishing articles outlining both the pro’s and con’s of testing natural killer cells. Unfortunately, many people opposed to the testing only cite the publication that argues against it. That being said, not everyone requires testing for natural killer cell activation – it should be reserved for certain patients that have already demonstrated an implantation issue. And treatment of these individuals, should their test be positive, has been successful in thousands of anecdotal cases.