In today’s society, with the fast pace, stress, and many environmental toxins, urban life is not just hectic; it also affects the ability of modern families who want to have children. They may face difficulties or limitations due to time constraints and economic factors. As a result, modern parents turn to science to help them choose the sex of their child or address fertility issues. However, even with both natural and scientific methods, miscarriages can occur, despite being healthy and well-prepared, because our bodies have other mechanisms that can lead to miscarriage.
We generally accept that preparing for pregnancy involves just blood tests and routine physical exams. However, one thing we never check is the quantity and quality of NK cells. Why should we check them? What does the test reveal? If abnormalities are found, what should be done to reduce the risk of miscarriage?
From a study conducted since 1999, Professor Yamamoto and colleagues from Teikyo University School of Medicine, Tokyo, Japan, have been investigating NK cell levels. Normally, miscarriage is a natural mechanism that prevents abnormal or incomplete embryos from developing further from the chromosomal level during pregnancy. However, a faulty miscarriage occurs when a normal embryo or an abnormal embryo is able to develop further. This led Professor Yamamoto to study miscarriages in embryos with normal and abnormal chromosomes to see if there is a correlation with internal mechanisms or certain types of white blood cells. White blood cells, particularly NK cells, have been studied extensively and are known to be involved in pregnancy and miscarriages. However, no one has studied their proportion in the bloodstream to find a correlation. The study aims to find CD56.+ NK cells using Flow cytometry revealed the quantity of CD56.+ NK cells in normal fetal miscarriage differ in quantity from those in abnormal fetal miscarriage. Therefore, the proportion of NK cells affects the treatment of the fetus in the mother’s womb.
Then, in the year 2016, Professor Marigoula Varla-Leftherioti published “Natural Killer (NK) Cell Receptors and their Role in Pregnancy and Abortion” in the Journal of Immunobiology. It was found that NK cells (dNK CD3-CD56brightCD16dim/-–) It affects pregnancy in the first trimester and studies the mechanism of miscarriage. It was found that KIR receptors found in NK cells and T lymphocytes cause NK cells to destroy embryos at the trophoblast (helping embryos to be moist and the tissue of the embryo to grow into a placenta), resulting in lysis and causing the embryo to be expelled and miscarriage.
From a study investigating the relationship between NK cell levels and the mechanism of NK cells affecting miscarriage, the cut-off value could not be determined until 2018. Professor Hajar Adib Rad conducted a study in Iran, where miscarriage is a common issue. The study involved 80 pregnant women and found that an NK cell level of ≥3.4% (p < 0.015) increased the risk of miscarriage.
In 2020, Professor Yu-Han Meng and colleagues conducted a study on recurrent miscarriage in women of reproductive age, investigating whether it was caused by NK cells present in the uterus up to 70%. This led to the search for ways to control or create a balanced state of NK cells in terms of both quantity and health.
Then, in the year 2016, Professor Marigoula Varla-Leftherioti published “Natural Killer (NK) Cell Receptors and their Role in Pregnancy and Abortion” in the Journal of Immunobiology. It was found that NK cells (dNK CD3-CD56brightCD16dim/-–) It affects pregnancy in the first trimester and studies the mechanism of miscarriage. It was found that KIR receptors found in NK cells and T lymphocytes cause NK cells to destroy embryos at the trophoblast (helping embryos to be moist and the tissue of the embryo to grow into a placenta), resulting in lysis and causing the embryo to be expelled and miscarriage.
From a study investigating the relationship between NK cell levels and the mechanism of NK cells affecting miscarriage, the cut-off value could not be determined until 2018. Professor Hajar Adib Rad conducted a study in Iran, where miscarriage is a common issue. The study involved 80 pregnant women and found that an NK cell level of ≥3.4% (p < 0.015) increased the risk of miscarriage.
In 2020, Professor Yu-Han Meng and colleagues conducted a study on recurrent miscarriage in women of reproductive age, investigating whether it was caused by NK cells present in the uterus up to 70%. This led to the search for ways to control or create a balanced state of NK cells in terms of both quantity and health.
Currently, we are familiar with the term “cell therapy” or treatment using the immune system, which is a new option for treating diseases that cannot be cured by medication alone. Whether it’s using stem cell therapy to treat blood disorders such as thalassemia or leukemia, in 2022, countries in Europe, America, Korea, China, and Japan have rapidly advanced in the use of cell therapy for patients or even in the wellness sector for people preparing for pregnancy or at risk of miscarriage. Is there an option like this available for them?
In 2020, Professor Carolyn B. Coulam and colleagues from Rosalind Franklin University of Medicine and Science, North Chicago, USA, utilized intravenous immunoglobulin (IVIG) therapy, although previous studies had shown that it was not as successful in treating miscarriages as expected. However, Professor Carolyn B. Coulam decoded this mystery and found that when IVIG therapy is administered correctly, it can suppress NK cells, preventing them from playing a role in miscarriages.
Professor Carolyn B. Coulam found that miscarriages can occur due to various factors, such as the mother’s physical condition including the uterus, hormones, immune system, blood flow, and the health of the fetus. The use of intralipid therapy administered intravenously is suitable for targeting NK cells (Cytotoxic) and pro-inflammatory cytokines. Therefore, Professor Carolyn B. Coulam conducted tests to measure the quantity of Cytotoxic NK cells in uterine tissue, as well as in the bloodstream, in two groups of women: those who were pregnant and those who were not. It was found that in the continuously pregnant group, the quantity of NK cells in the bloodstream and uterine tissue was lower than in women who experienced miscarriages.
And it was found that intralipid can increase the chances of pregnancy in both normal conditions and in increasing embryo implantation (IVF), reduce miscarriage rates, from the effects of NK cells and pro-inflammatory cytokines. However, it cannot treat miscarriages caused by other conditions such as hormones, maternal physical limitations, blood flow, and fetal health.
Therefore, before pregnancy or embryo implantation, it is advisable to check the quantity and quality of NK cells to reduce the risk of miscarriage from pregnancy.
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Reference documents
Sugiura-Ogasawara, M., Ozaki, Y., Sonta, S. I., Makino, T., & Suzumori, K. (2005). Exposure to bisphenol A is associated with recurrent miscarriage. Human reproduction, 20(8), 2325-2329.
Lédée, N., Vasseur, C., Petitbarat, M., Chevrier, L., Vezmar, K., Dray, G., … & Chaouat, G. (2018). Intralipid® may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation. Journal of Reproductive Immunology, 130, 18-22.
Rad, H. A., Basirat, Z., Mostafazadeh, A., Faramarzi, M., Bijani, A., Nouri, H. R., & Amiri, S. S. (2018). Evaluation of peripheral blood NK cell subsets and cytokines in unexplained recurrent miscarriage. Journal of the Chinese Medical Association, 81(12), 1065-1070.
Yamamoto, T., Takahashi, Y., Kase, N., & Mori, H. (1999). Role of decidual natural killer (NK) cells in patients with missed abortion: differences between cases with normal and abnormal chromosome. Clinical & Experimental Immunology, 116(3), 449-452.
Fu, Y. Y., Ren, C. E., Qiao, P. Y., & Meng, Y. H. (2021). Uterine natural killer cells and recurrent spontaneous abortion. American Journal of Reproductive Immunology, 86(2), e13433.
Varla-Leftherioti, M., & Keramitsoglou, T. (2016). Natural killer (NK) cell receptors and their role in pregnancy and abortion. J Immunobiol, 1, 1-6.