Any hope with recurrent implantation failure in IVF?
Reproductive Health Fertility IVF

Any hope with recurrent implantation failure in IVF?

Dr. Ralph Papas
Dr. Ralph Papas

In 10 seconds? Despite huge advances in in-vitro fertilization (IVF) technology, still around 10% of patients suffer what is called: “recurrent implantation failure” or RIF, a condition characterized by failure to achieve a pregnancy after repeated and multiple IVF embryo transfers.

So, what is RIF? Just a few days after conception happens, the healthy embryo must find a welcoming endometrium (the lining of the uterus) to implant, for pregnancy to occur. Embryo implantation is still poorly understood in research and there is no consensus in the scientific literature on how to define recurrent implantation failure and several definitions exist. Generally, RIF is diagnosed based on the number of unsuccessful IVF cycles (the process of ovarian stimulation, egg and sperm retrieval, fertilization, and embryo transfer), the number of embryos transferred, or a combination of both factors.

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OK, I'm not a researcher but I might be paying for IVF. How should I understand what is considered a 'failure'? OK, it’s perhaps important to mention at least, the latest definition by the European Society of Human Reproduction and Embryology’s (ESHRE) Preimplantation Genetic Diagnosis Consortium. They came up with a definition of RIF as more than 3 failed embryo transfers with high-quality embryos or the failed transfer of 10 or more embryos in multiple transfers.

Thanks for clearing that up, but what are its causes? The origins of Recurrent Implantation Failure are also obscure, perhaps because three different players are involved: the female partner, the male partner as well as the embryo. Researchers like to note the primary determinant of successful conception is that the embryo has the right pair of chromosomes (remember the number from our earlier Digest? 46 in total, 23 from both parents each. However, as this study mentions, less than 60% of such (so-called euploid) embryos survive and result in an ongoing pregnancy.

Embryo implantation. Source: Achache and Revel, 2006
Embryo implantation. (A) Endometrium proliferates under estrogen enhancement. (B) Progesterone leads to endometrial differentiation. (C) The blastocyst enters the uterus. (D) Mucin-1 prevents adhesion to endometrial areas with poor implantation chances. (E) The blastocyst is attracted to the optimal implantation spot. (F) The blastocyst attaches to the endometrial pinopods for further successful implantation. Source: Achache and Revel, 2006

So, with a healthy embryo, we are less than halfway to success. Why? When good-quality embryos fail to implant repeatedly, an endometrial cause is often suspected but that is not always easy to confirm clinically. However, the causes are more complex than a problem with endometrium. Structural components – get ready for a carpet bombing of Latin words - such as polyps, submucosal myomas, intrauterine synechiae, and uterine septums* have been found to have detrimental effects on successful implantation. (* outgrowths, benign tumors of the uterine muscle, scar tissues within the uterine cavity, and an extra wedge in the uterus). In addition, generalized conditions, such as endometriosis, have demonstrated effects on various individual components of implantation. And, other systemic disruptions may have an impact on the endometrium in a more obscured way. Obesity, for instance, has been associated with altered endometrial gene expression and reduced pregnancy rates. While some of these pathologies may be obvious in a patient with RIF, routine testing often cannot establish the causes in many patients.

But what is generally done in those cases? Patients undergoing in vitro fertilization (IVF) have ongoing ultrasound evaluation of the endometrium. When an endometrium does not thicken enough, this could predict lower chances of embryo implantation. Ultrasound could also suggest the possibility of an additional pathology. However, many patients with RIF exhibit normal endometrial thickness and may have other, yet unknown processes causing implantation failure. Complete evaluation typically requires multiple forms of recently introduced additional endometrial testing and sampling.

Tell me more about these new endometrial tests? The establishment of endometrial receptivity is primarily coordinated by the female hormones, estrogen, and progesterone. Estrogen stimulates endometrial proliferation (i.e the thickening of the interior lining of the uterus), with the resulting thickness directly correlated to success in assisted reproduction. Progesterone is also necessary for the establishment of what is called: the “window of implantation”. These new tests are designed to examine the window of implantation, in other words, whether the endometrium is receptive enough for the embryo on the genomic level.

So, what can be done if I experience recurrent implantation failure? Obviously, every situation of RIF is different, and the management should be tailored accordingly. If the endometrium is found to be pre-or post- receptive (not quite ready or past the optimum implantation period) on “window of implantation testing”, then the day of embryo transfer can be changed correspondingly. Occasionally, endometrial sampling can reveal chronic sub-clinical infections and imbalances that can be treated by targeted antibiotic and/or probiotic therapies as studied have highlighted an association between implantation failure and an abnormal microbiome in the uterus lining. However, a significant portion of these tests will not help explain the cause of repeat failure. Therefore, many studies have examined experimental therapies for these “unexplained” RIF cases.

Like what? Intra-uterine hCG (Human Chorionic Gonadotropin) is one of these frequently cited additional therapies. Other similar therapies include Endometrial scratching, Growth Hormone, PRP (Platelet-Rich Plasma), and GCSF injections (Granulocyte Colony-stimulating factor). Steroids have also been tried and have been found to be potentially beneficial in the presence of signs of an immune-inflammatory reaction in the endometrium.

Is there hope for these cases?

Yes… In fact, despite the lack of full consensus and the complexity of the condition, new studies are strongly implicating problems affecting the endometrial cavity in RIF as suggested above.

And many of such cases respond to treatment, despite the problem caused by a frequently obscure diagnosis.

So yes, there is always hope that despite recurrent implantation failure, women undergoing IVF will be able to get pregnant.

Dr. Ralph Papas has distilled 9 research papers saving you 31.5 hours of reading time.

The Science Integrity Check of this 3-min Science Digest was performed by Dr. Mónica Faut.

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