Infertility affects approximately 15% of the reproductive age population, which is currently estimated at about 7.5 million people. Assisted Reproductive Technology (ART) has made significant improvements since the original In Vitro Fertilization (IVF) success in 1978. Yet, it is estimated that 50% of embryos generated with IVF are still unable to successfully implant. Even with the introduction of preimplantation genetic screening (PGS), euploid embryos are still not successful in achieving a live birth at least 25-30% of the time. The pathology of recurrent implantation failure, defined as the transfer of 2-4 high quality embryos (arguably less if PGS tested) without success, is an active area of investigation. The question plaguing both Repeated Implantation Failure (RIF) patients and their providers remains… Why isn’t this working?

Implantation failure of euploid embryos can be due to an underdeveloped lining, hydrosalpinges, endometriosis, and infection. It is estimated that 10% of IVF patients will have RIF. Although it is clear that the immune system plays a role in implantation, our fields’ understanding of the physiology, let alone pathophysiology of this process, remains incomplete. A recent meta-analysis of twenty high quality trials totaling 1137 women assessed multiple immune therapies including paternal leukocyte immunization, intravenous immune globulin (IVIG), trophoblast membranes and third party donor leukocytes revealed no increase in live birth rates with any intervention when compared with placebo or no treatment (Wong, 2014). Despite this, immunologic treatments remain a primary concern for many patients based on websites with little data to support their treatment efficacy.

Impact of the immune system on implantation can be broken down into three areas: helper t cell immunity, natural killer cells, and autoantibodies.

There are two types of helper t cells (TH1 (pro-inflammatory and include INF-gamma/ TNF-alpha) and TH2 (anti-inflammatory). Pregnancy is a TH2 dominated state mediated by increased progesterone. Animal models have suggested that alteration of the ratio between TH1 and TH2 can lead to increases in miscarriage. Yet, the translation of this into clinical practice is still a ways off. Immunomodulators such as TNF-alpha blockers or IVIG are able to increase TH2 dominance, unfortunately, as of yet, the therapy has not yet shown to decrease RIF or Recurrent Pregnancy Loss (RPL).

Currently, assessment of uterine immunology is often based on screening peripheral NK cells. Uterine NK cells are phenotypically different than those circulating in blood based on having different antigens present. Uterine NK cell function is largely unknown and not reflected in peripheral measurements. NK cells are a heterogeneous group of cells in which, killer immunoglobin-like receptors (KIRs) determine NK cell function. Placentation is regulated by KIRs expressed by uNK cells and HLA molecules from the fetal trophoblasts. Studies have shown that woman with a particular KIR haplotype are at increased risk of recurrent miscarriage, preeclampsia, and growth restriction. Clinical applications of these findings are still evolving.

Autoantibodies such as antiphospholids are an attractive theory based on relationship of APA and RPL. Yet, multiple large meta-analyses have failed to show a role of APA in RIF. Thus screening for thrombophilias in patients with RIF is not recommended by American Society of Reproductive Medicine (ASRM).

Although immunomodulation therapies such as glucosteroids, heparin, aspirin, IVIG and intralipids are utilized in clinical REI practice there is not LEVEL 1 evidence to support these treatments. Some of these medications, in particular IVIG, also have significant side effects, such as, infection and cost. At Fertility Centers of Illinois we did a retrospective study of 127 patients using intralipids with a history of RIF/RPL undergoing ART treatment, there was not a significant difference in clinical pregnancy rates when comparted to RIF’s controls. Furthermore, we conducted a cost-analysis from a societal perspective which demonstrated that despite being an inexpensive treatment, intralipids were not cost-effective due to their limited efficacy. This work is being presented at the American Society of Reproductive Medicine in San Antonio later this year.

As with all aspects of medicine, using treatments with minimal data supporting their practice is problematic. As provider/patient(s) it is difficult to not have answers as to why pregnancy is not occurring. As IVF treatments continue to improve, improved understanding of the role of the immunomodulators to enhance implantation will likely be a part of this.


References

The Practice Committee of the American Society for Reproductive Medicine. Antiphospholipid antibodies do not affect IVF success. Fertility and Sterility. 2000;90(5 suppl): S172-3.

Franasiak JM and RT Scott. Contribution of immunology to implantation failure of euploid embryos. Fertility and Sterility.2017;107:1279-83.

Alecsandru D and JA Garcia-Velasco. Why natural killer cells are not enough: a further understanding of killer immunologlobin-like receptor and human leukocyte antigen. Fertility and Sterility. 2017; 107:1273-8.

Hiby SE, Apps R, Sharkey AM et al. Maternal activating KIRs protect against human reproductive failures mediated by fetal HLA-C2. J Clin Invest 2010; 120:4102-10.
Wong LF. Immunotherapy for recurrent miscarriage. Cochrane Database of SystematicReviews. 2014.