The Role of NK cells in Infertility
Natural Killer (NK) cells are a type of white blood cell that defend us from tumors, viruses and other potential invaders. After ovulation and during early pregnancy, NK cells comprise a major portion of the white blood cell population seen in the uterine lining. In early pregnancy, NK cells are highly concentrated at the maternal-fetal interface where the embryo is trying to implant. Unlike other invaders, “healthy” embryos secrete a molecule (HLA-G) that suppress uterine NK cells killing activity and spares them from being rejected. NK cells also make modulating factors known as cytokines, which help dilate the maternal arteries supplying the developing fetus with the necessary blood, nutrients and oxygen. In the presence of NK cell hyperactivation, the NK cells do not spare the “healthy” embryo, and this results in a failed implantation, biochemical pregnancy or early miscarriage. Activated NK cells can move freely from the uterine lining into the peripheral blood where their toxicity can be measured through a blood test. Most miscarriages (70%) or failed IVF cycles are due to an error of chromosomal division inside the egg/embryo. Still, in a small sub-group of patients, IVF fails
even when the embryo is chromosomally normal (such as one called normal with PGT-A) and the uterine lining is receptive (such as a transfer timed by ERA results). In this small subgroup of women, failed implantation may be linked to hyperactivation of NK cells. Multiple observational studies have shown a reduction in immune implantation failure with adequate treatment. While gold standard double-blind randomized studies are lacking, our long term clinical experience with immune treatment of those selected cases has been positive. Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:
Unexplained IVF failures despite normal PGT-A results and ERA timing Endometriosis Recurrent early miscarriage despite chromosomally normal embryos Family history of autoimmune diseases (e.g. rheumatoid arthritis, lupus, hypothyroidism).
About half of women with antibodies to their own thyroid tissues (antithyroglobulin or anti-microsomal antibodies) have activated Natural Killer cells in their blood. Many of these women still have normal thyroid function when they present with reproductive failure manifesting as unexplained infertility, recurrent IUI and IVF failure, or repeated early pregnancy loss. The anti-thyroid antibodies are not the cause of immune implantation failure. They act as markers of an underlying immunologic dysfunction that also causes NK cell hyperactivation. In those women, a family or personal history of hypothyroidism is common. Occasionally, the auto-immune activity against the thyroid gland causes collateral damage to the ovaries and this results in decreased ovarian reserve (lower AMH). Patients with endometriosis have immunologic abnormalities which may explain their higher rate of implantation failure. In these cases, implantation may be hindered by the presence of hyperactivated uterine NK cells that attack the invading embryo early in the implantation process. This attack may cause a “minimiscarriage” before the pregnancy test turns positive. NK cells seem to play a vital role in implantation. Presently, these immunologic markers can only be adequately measured by a few highly specialized
reproductive immunology laboratories in the United States. The aim of the test is to measure the % killing activity of these NK cells, not their concentration. Other immunologic issues, like anti-phospholipid antibodies (APLA), cause late miscarriages rather than failed IVF. In most cases, the presence of APLA and/or their treatment with anticoagulants does not improve implantation. Instead, in patients with hyperactivated NK cells, Intralipid therapy, along with low dose steroid therapy, should be initiated more than 1 week prior to embryo transfer to suppress activated NK cells and reduce the risk of implantation failure. This infusion is a safe low-cost nutritional product containing soybean oil and egg yolk phospholipids that “saturate” NK cells and suppress their killing activity. It is administered every 3 weeks until a fetal heartbeat is detected at which time the rate of miscarriage is less than 5%. Unfortunately, the treatment of immune implantation failure requires IVF. In natural conception, the NK cells have already attacked the embryo by the time the pregnancy test turns positive. Intralipid therapy takes 7-10 days to suppress NK cell activity and starting treatment so late is usually ineffective. Furthermore, many people with recurrent pregnancy losses benefit from pre-implantation genetic testing of their embryos prior to implantation. The selective use of immunotherapy has, on numerous occasions, enabled us to achieve successful pregnancies in patients who had suffered multiple unexplained IVF failures. If you have any questions or would like to schedule an appointment, please contact us at 972-566-6686 today. Visit: infertility/
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