Implantation potential: why is your innovative solution needed?
Learn about the current advancements in improving implantation potential and how the MIP can help
Embryo implantation is a well‑orchestrated
process and its success relies on the presence of a healthy embryo, a receptive
endometrium, appropriate embryo-endometrial cross‑talk and adequate maternal immune protection.1 Despite the significant
advances in assisted reproductive technology (ART), the implantation rate
following in vitro fertilization – embryo transfer (IVF-ET) remains
relatively low, which is a big impediment to successful pregnancy.2 In particular, pregnancy loss
following ART is attributed to an implantation failure rate of 50%.2
To address this issue, research
over the last few years has focused on identifying innovative ways of improving
endometrium receptivity and embryo invasion, in order to achieve successful
implantation. However, there is not adequate support for these innovations to
reach patients.
What advances focus on the
endometrium?
One of the most important factors that regulates the complex process of implantation is the hormone human chorionic gonadotropin (hCG), produced by the pre-implantation embryo and the endometrial cells.3 hCG modulates tissue remodelling that is essential for angiogenesis, placentation, implantation, receptivity and tolerance and that it also regulates maternal immune response during implantation.3 Therefore, administration of hCG appears to be a beneficial strategy for improving IVF outcomes. Navali et al. in 2016 showed that intrauterine administration of hCG immediately after oocyte retrieval improves pregnancy outcomes.3 According to a recent meta-analysis of randomised controlled trials intrauterine hCG injection before embryo transfer achieves higher implantation potential and live birth rates (LBRs), with the outcome being timing- and dosage-dependent.2
Another emerging method for
improving implantation potential in women with recurrent implantation failure
(RIF) due to refractory endometrium is the treatment with autologous
platelet-rich plasma (PRP).1 The PRP contains factors,
including the vascular endothelial growth factor (VEGF) and transforming
growth factor (TGF), that exert favourable proliferative, anti-apoptotic
effects in the endometrium endothelieum.1 Notably, in 2019 a pilot
study by Madhavan et al. challenged the fact that intrauterine administration of PRP improves
the implantation rates in patients undergoing frozen embryo transfer.1
The use of autologous peripheral
blood mononuclear cells (PBMCs) through intrauterine administration, to treat
women with RIF is also being widely discussed.4 PBMCs consist of a mix of T
lymphocytes, B lymphocytes and monocytes that have the ability to control the
production of several cytokines and have demonstrated effectiveness in
supporting blastocyst invasion and endometrium receptivity in vitro and
optimised IVF outcomes in vivo.4 Systematic reviews and
meta-analyses have yielded inconsistent data, with regards to the correlation
of PBMCs use and live birth rates in IVF, therefore further studies are
required to validate or disprove the hypothesis.4,5
What advances focus on the
embryo culture?
Advances are seen not only in the
clinic, but also in the embryology lab. Metabolomic studies have helped to
understand the needs of the pre-implantation embryo at each development stage and
contributed to remarkable progress in the development of culture media for ART.6 This knowledge offers the
benefit of culture media optimization in order to develop embryos with high
implantation potential.
Numerous aspects of embryo
culture can impact implantation potential, including temperature, sequential vs
one-step culturing system, dynamic cultures and culture media composition.7 A Cochrane review suggested
an improvement in clinical pregnancy rates after the addition of the compound hyaluronan
into the transfer medium, however the results are inconsistent and a
retrospective case-control study challenged this approach.8,9
Moreover, a randomized clinical
trial from 2013 provided evidence that the addition of granulocyte-macrophage
colony-stimulating factor (GM-CSF) to embryo culture medium benefits ongoing
implantation and results in a significant increase in survival of transferred
embryos to week 12 and live birth.10 These findings indicate that GM-CSF
may be particularly efficacious in women with previous miscarriage.10 Regarding culture
consistency, it is also noteworthy that several studies indicate improved
embryo development, implantation and pregnancy rates in reduced oxygen
conditions.7
How can the MIP help?
There is a plethora of
advancements in improving implantation rates in ART, either by focusing on the
endometrium or by optimizing the culture media, and thereby high potential to
transform clinical practice. However, the number of those innovations that make
it into the clinic remains low.
Researchers may not receive
adequate support and funding and if they feel too disconnected from each other,
this prevents collaboration. Even the best idea in the world will not be
developed into a product for patients without the right resources and
expertise.
The MIP supports the development
of such technologies and offers both the right network and the enabling technologies to meet such
a major medical need.
Apply today to join the Medical
Innovation Program for human reproduction!
References
1. Madhavan A, Naidu P, Rani K, Kaur J,
Mahajan N. Intrauterine autologous platelet-rich plasma therapy to improve
implantation rates in patients undergoing frozen embryo transfer: A pilot
study. Onco Fertil J. 2019. doi:10.4103/tofj.tofj_11_18
2. Gao MX, Jiang XY, Li B, et al.
Intrauterine injection of human chorionic gonadotropin before embryo transfer
can improve in vitro fertilization-embryo transfer outcomes: a meta-analysis of
randomized controlled trials. Fertil Steril. 2019;112(1):89-97.e1.
doi:10.1016/j.fertnstert.2019.02.027
3. Navali N, Gassemzadeh A, Farzadi L, et
al. Intrauterine administration of hCG immediately after oocyte retrieval and
the outcome of ICSI: A randomized controlled trial. Hum Reprod. 2016.
doi:10.1093/humrep/dew236
4. Maleki-Hajiagha A, Razavi M, Rezaeinejad
M, et al. Intrauterine administration of autologous peripheral blood
mononuclear cells in patients with recurrent implantation failure: A systematic
review and meta-analysis. J Reprod Immunol. 2019.
doi:10.1016/j.jri.2019.01.001
5. Yakin K, Oktem O, Urman B. Intrauterine
administration of peripheral mononuclear cells in recurrent implantation
failure: a systematic review and meta-analysis. Sci Rep. 2019.
doi:10.1038/s41598-019-40521-w
6. Gruber I, Klein M. Embryo culture media
for human IVF: which possibilities exist? J Turkish Ger Gynecol Assoc.
2011. doi:10.5152/jtgga.2011.25
7. Swain JE, Carrell D, Cobo A, Meseguer M,
Rubio C, Smith GD. Optimizing the culture environment and embryo manipulation
to help maintain embryo developmental potential. Fertil Steril. 2016.
doi:10.1016/j.fertnstert.2016.01.035
8. Bontekoe S, Heineman MJ, Johnson N,
Blake D. Adherence compounds in embryo transfer media for assisted reproductive
technologies. Cochrane Database Syst Rev. 2015.
doi:10.1002/14651858.CD007421.pub3
9. Chun S, Seo JE, Rim YJ, Joo JH, Lee YC,
Koo YH. Efficacy of hyaluronan-rich transfer medium on implantation and
pregnancy rates in fresh and frozen-thawed blastocyst transfers in Korean women
with previous implantation failure. Obstet Gynecol Sci. 2016.
doi:10.5468/ogs.2016.59.3.201
10. Ziebe S, Loft A, Povlsen BB, et al. A
randomized clinical trial to evaluate the effect of granulocyte- macrophage
colony-stimulating factor (GM-CSF) in embryo culture medium for in vitro
fertilization. Fertil Steril. 2013. doi:10.1016/j.fertnstert.2012.12.043