Immunotherapy

Natural killer cell testing and immune therapy

There are several factors that can cause embryo implantation to fail, including

  • Genetic causes
  • Anatomical causes
  • Endocrine causes
  • Haematologic causes
  • Immunologic causes
  • Miscellaneous causes.

In most cases, it is the result of a chromosomal abnormality (known as aneuploidy) within the embryo. In some cases, it can be a combination of the above causes. In the past decade, there has been considerable efforts and research trying to identify possible immunologic causes for poor fertility treatment outcome.

ImmunologyWhat happens around implantation?

The embryo is formed of two cell lines (the inner cell mass and the trophectoderm). The inner cell mass contains the cells that form the baby and the trophectoderm contains the cells that will form the fetal part of the placenta.  Implantation is a complex process that involves interaction between the trophectoderm and the womb lining (endometrium). During this process there is mutual exchange of substances and chemicals. This is sometimes referred to as ‘embryo-maternal cross talking’. Successful implantation is the first crucial step in achieving a pregnancy.

What do I need to know about Natural Killer cells (NK cells)?

NK cells are immune cells that belong to a subcategory of white blood cells called ‘Lymphocytes’. They provide the body with protection against virally infected cells and potential cancerous cells. NK cells are produced by the bone marrow and then they move to the blood circulation to play a role in the body natural defence mechanisms. Some of the NK cells will migrate to various organs including gastrointestinal tract, liver and the uterus where they undergo specific changes that render them as one of the immunological defence barriers in those tissues. In the uterine lining after ovulation and in early stages of pregnancy; NK cells account for more than 80% of the white blood cell population. NK cells produce and respond to a variety of chemical substances called ‘cytokines’.

Is there strong evidence to support that abnormal NK cells are associated with poor fertility or pregnancy outcome?

This matter is controversial within the medical field. NK cells are the most abundant immune cells in the womb lining (endometrium) at the time of implantation. There are different types of NK cells.  It has been speculated that an imbalance in the cytokines and the killing activity of the NK cells can have a negative impact on implantation or the progression of a healthy pregnancy.

Results published in the medical literature have been contradictory; however, it is thought that recurrent miscarriages and recurrent implantation failures that cannot be explained by routine investigations might have an immune based cause.

The Human Fertilisation and Embryology Authority (HFEA), the Royal College of Obstetricians and Gynaecologists (RCOG), Science Advisory Committee and the American Society of Reproductive Medicine (ASRM) all agree that there is no strong evidence at the moment to justify immune testing and treatment in the context of fertility failure and recurrent miscarriages

 

“There is no convincing evidence that a woman’s immune system will fail to accept an embryo due to differences in their genetic code. In fact, scientists now know that during pregnancy the mother’s immune system works with the embryo to support its development” HFEA.

These tests and treatments are outlined as an additional treatment option by the HFEA and have currently been deemed as red in the HFEA traffic light system for additional treatment options as there is no evidence to show that it can improve live birth rates. Red-rated add-ons are considered by the HFEA experimental in nature. Please refer to the treatment add-ons page of the HFEA website6.

Are the NK tests offered routinely at CRGH?

NK cell tests are not routinely offered to all patients seeking fertility treatment as the majority of failed fertility treatments and miscarriages are secondary to a chromosomal abnormality in the embryo and not immune in origin. You will have the chance to discuss carrying out those tests with your doctor during the consultation if you have a history of recurrent miscarriages, recurrent implantation failures or if you have a personal history of autoimmune disorders (such as lupus, rheumatoid arthritis, ulcerative colitis, auto-immune thyroid issues, Crohn’s disease).

As NK cell tests are not evidence based with respect to improving livebirth rates and are optional, the clinic will only offer the tests when your consultant deems it appropriate for your treatment. The CRGH will offer the tests in order to reduce the chance of miscarriage and/or implantation failure.

What are the NK tests available at CRGH?

NK cells can be checked in the peripheral blood or in the womb lining (endometrium).  At CRGH we offer both tests. Endometrial NK cells are checked by carrying out a minor procedure (a “scratch” of the lining of the womb) between days 15-25 of the period. The sample retrieved will be sent to the laboratory for analysis. NK cells test is performed on specific days of the week, so please confirm with the clinic before booking the test. NK cells in the blood are not a good reflection about the NK cells in the lining of the womb. However, there is some evidence to suggest an association between NK cell activity in the blood and pregnancy loss1,7,8. In most cases the blood test and the “scratch” of the lining of the womb are carried out on the same day.

What are the treatment options that are offered at the CRGH for elevated NK cells?

Several immunosuppressive treatments have been used in this context. Three treatment options are currently available at the CRGH.

  1. Oral steroid treatment (Prednisolone)
  2. Intralipid infusion
  3. Intravenous immunoglobulin (IVIg) infusion

No results from randomised clinical trials are available to show a clear benefit for patients receiving immunomodulatory treatment versus those who have not. However, several studies suggest that there may be a benefit of immunological treatments compared to no treatment at all7-21. It is important to note that the RCOG does not recommend testing or immunological treatment except in the realm of experimental medicine.

The Royal College also mentions that:

“Women undergoing uterine NK cell testing should understand that there is as yet, no proven effective treatment for those with what may be considered abnormal results, although preliminary data suggest a possible positive effect of prednisolone.”22

 

Steroid (Prednisolone) Treatment

Steroid (Prednisolone) is a commonly used medication in the treatment of autoimmune diseases. It acts by suppressing the immune system. The role of immune mediators in the process of embryo implantation has not been confirmed. However, there is some evidence to suggest that steroid treatment may be beneficial in improving the implantation potential of your embryo(s)9-13. As the use of steroids is not evidence based with respect to improving livebirth rates and is optional, the clinic will only offer it when your consultant deems it appropriate for your treatment. The CRGH will offer steroid in order to reduce the chance of having a miscarriage and/or implantation failure. In case you choose to take this medication, you will start Prednisolone when you commence progesterones.

 

Intralipid®

Intralipid® has been used for improving implantation in patients with high natural killer cell activity, but there is limited information available regarding its efficacy11,14-16. Unlike other medications used to suppress natural killer cell activity, Intralipid® is not a human derived product. The use of Intralipid® has not been recommended by the HFEA or the RCOG. As the use of Intralipid® is not evidence based with respect to improving livebirth rates and is optional, the clinic will only offer it when your consultant deems it appropriate for the treatment. The CRGH will offer Intralipid® in order to reduce the chance of having a miscarriage and/or implantation failure.

 

Intravenous Immunoglobulin (IVIG) (Privigen® 20g/200ml)

IVIG is concentrated and highly purified human immunoglobulins (antibodies) primarily IgG (immunoglobulin G). IVIG is prepared from pooled human blood donors. There is evidence to suggest that IVIG may be a useful treatment option for certain patients such as those with previous IVF failures and/or abnormal preconception immune profile7-8,18-21. As the use of IVIG is not evidence based with respect to improving livebirth rates and is optional, the clinic will only offer it when your consultant deems it appropriate for your treatment. The CRGH will offer IVIG in order to reduce the chance of having a miscarriage and/or implantation failure.

 

Contact us

If you would like to book an appointment with one of our doctors you can:

  • Speak to the booking team on +44 (0)20 7837 2905  (Mon – Fri 8.30am – 6pm)
  • Email us on info@crgh.co.uk 
  • Visit our Appointments page, fill out the contact form and a member of the team will be in touch

 

References:

  1. Toth B, Vomstein K, Togawa R, Bottcher B, Hudalla H, Strowitzki T, et al. The impact of previous livebirths on peripheral and uterine natural killer cells in patients with recurrent miscarriage. Reprod Biol Endocrinol 2019; 31:17: 72
  2. El-Azzamy H, Dambaeva S, Katukurndage D, Garcia M, Skariah A, Hussein Y et al. Dysregulated uterine natural killer cells and vascular remodelling in women with recurrent pregnancy losses. Am J Reprod Immunol 2018; 80:13024
  3. Kuon R, Weber M, Heger J, Santillan I, Vomstein K, Bar C, et al. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol 2017; 78(4).doi:10.1111/aji.12721
  4. Junovich G, Azpiroz A, Incera E, Ferrer C, Pasqualini A, Gutierrez G. Endometrial CD 16+ and CD16- NK cell count in fertility and unexplained infertility. Am J Reprod Immunol 2013; 70:182-9.
  5. Quenby S, Farquharson R. Uterine natural killer cells, implantation failure and recurrent miscarriage. Reprod Biomed Online 2006; 13:24-8.
  6. https://www.hfea.gov.uk/treatments/treatment-add-ons/
  7. Winger E, Reed J, Ashoush S, El-Toukhey T, Ahuja S, Taranissi M. Elevated preconception CD56+16+ and/or Th1:Th2 levels predict benefit from IVIG therapy is subfertile women undergoing IVF. Am J Reprod Immunol 2011; 66; 394-403.
  8. Winfer E, Reed J, Ashoush S, El-Toukehy T, Ahuja S, Taranissi M et al. Degree of TNF-α/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adlimumab and IVIG. Am J Reprod Immunol 2011;65:610-8.
  9. Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Feril Steril 2005: 84:980-4.
  10. Ledee N, Prat-Ellenberg L, Petitbarat M, Chevrier L, Simon C, El Irani et al., Impact of prednisolone in patients with repeated implantation failures: beneficial or deleterious. J Reprod Immunol 2018; 127:111-115.
  11. Ledee N, Petitbarat M, Chevrier L, Vitoux D, Vezmar K, Rahmati M et al. The uterine immune profile may help women with repeated unexplained embryo implantation failure after in vitro fertilization. Am J Reprod Immunol 2016; 75:388-401.
  12. Nyborg K, Kolte A, Larsen E, Christiansen O. Immunemodulatory treatment with intravenous immunoglobulin and prednisolone in patients with recurrent miscarriage and implantation failure after in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2014; 102:1650-5.
  13. Litwicka K, Arrivi C, Varricchio M, Mencacci C, Greco E. In women with thyroid autoimmunity, does low dose prednisolone administration compared with no adjuvant, improve in vitro fertilization clinical results. J Obstet Gynaecol Res 2015; 41: 722-8.
  14. Ledee N, Vasseur C, Petitbarat M, Chevrier L, Vezmar K, Dray G et al. Intralipid may represent a new hope for patients with reproductive failures simultaneously an over-immune endometrial activation. Am J Reprod Immunol 2018; 130: 18-22.
  15. Zhou Ping, Wu H, Lin X, Wang S, Zhang S. The effect of intralipid on pregnancy outcomes in women with previous implantation failure in in vitro fertilization/intracytoplasmic sperm injection cycles: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2020; 252:187-192.
  16. Singh N, Davis A, Kumar S, Kriplani A. Eur J Obstet Gynecol Reprod Biol The effect of administration of intravenous intralipid on pregnancy outcomes in women with implantation failure after IVF/ICSI with non-donor oocytes: A randomized controlled trial Eur J Obstet Gynecol Reprod Biol 2019; 240:45-51
  17. Ledee N, Prat-Ellenberg L, Chevrier L, Balet R, Simon C, Lenoble C et al. Uterine immune profiling of increasing livebirth rate: a one to one matched cohort study. J Reprod Immunol 2017; 119:23-30.
  18. Clark D, Coulam C, Striker R. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer. J Assist Reprod Genet 2006; 23:1-13.
  19. Coulam C, Goodman C. Increased pregnancy rates after IVF/ET with intravenous immunoglobulin treatment in women with elevated CD56+ cells. Early Pregnancy 2000;4:90-8.
  20. Li J, Chen Y, Liu C, Hu Y, Li L. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: a systematic review and a meta-analysis. Am J Reprod Immunol 2013; 70:434-47.
  21. Virro M, Winger E, Reed J. Intravenous immunoglobulin for repeated IVF failure and unexplained infertility. Am J Reprod Immunol 2012;68:218-25.
  22. Immunological Testing and Interventions for Reproductive Failure (Scientific Impact Paper No. 5)

https://www.rcog.org.uk/en/guidelines-research-services/guidelines/sip5/

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