To begin, it is important to clarify that there is no universally accepted definition of implantation failure (IF).
According to Coughlan’s 2013 review, implantation failure was defined as failure to achieve a pregnancy following the transfer of at least four good-quality embryos over a minimum of three fresh or frozen cycles in a woman under the age of 40.
However, advances in assisted reproduction techniques in recent years, together with improved pregnancy rates, mean that many fertility centres now consider investigating implantation failure when pregnancy has not been achieved after two transfers of a single good-quality blastocyst.
What does successful embryo implantation depend on?
Successful embryo implantation depends on:
- The quality of the gametes.
- Embryo quality.
- Endometrial receptivity.
- The technique and appropriate timing of embryo transfer.
- The correct interaction between endometrial and embryonic factors during the implantation window, together with adequate luteal phase support.
Take the first step towards understanding your fertility
If you have been trying to conceive for some time or are unsure about what your next step should be, Clínica Fertia can help you.
Your first fertility consultation is free of charge and includes an initial assessment to provide you with clear, personalised guidance.
Request your First Visit Diagnostic Package and begin with an assessment tailored to your individual circumstances.
I want my free first consultation
What can cause implantation failure?
When considering the possible causes of implantation failure (IF), there are four main areas to investigate: uterine factors, endometrial factors, embryonic factors and immunological factors.
UTERINE FACTORS
When assessing uterine factors, both high-resolution 2D/3D ultrasound and hysteroscopy can help diagnose abnormalities within the uterine cavity.
The most common findings include polyps, small fibroids and uterine abnormalities, such as a subseptate or septate uterus, bicornuate uterus or dysmorphic uterus, as well as polypoid or hyperplastic endometrium, intrauterine adhesions and inflammatory conditions.
One such condition is chronic endometritis, which various authors have associated with implantation failure in approximately 30–60% of cases.
Other uterine abnormalities may include intramural fibroids. Depending on their size and location, and after ruling out other possible causes of implantation failure, surgery may be considered in some cases.
Another condition to consider is hydrosalpinx. The alkaline fluid contained within a hydrosalpinx includes cytokines, prostaglandins and other inflammatory molecules that may have a toxic effect on the embryo or negatively affect the endometrium. For this reason, surgery is generally recommended, either through salpingectomy or tubal occlusion.
ENDOMETRIAL FACTORS
With regard to endometrial factors, embryo implantation is understood as a balance between expressed and suppressed genes, controlled by steroid hormones and other local, autocrine and paracrine regulatory factors.
Thanks to omics technologies, it is possible to analyse a series of genes associated with endometrial receptivity and determine whether or not the endometrium is receptive.
The implantation window is the period during which the endometrium is receptive — in other words, when it has acquired the characteristics required for an embryo to attach and implant.
These studies can help coordinate embryo transfer with the time at which the endometrium is most receptive.
Both the ERA test and ER-Map can detect shifts in the implantation window, which are reported in 20–25% of women with implantation failure. This information can be used to personalise the timing of embryo transfer.
Another important aspect is the study of the endometrial microbiota.
The uterine cavity is not sterile. Hormonal changes, particularly those involving oestrogen and progesterone, favour the growth of lactobacilli. The microbiome of the female reproductive tract is predominantly composed of these bacteria.
A correlation has been observed between adverse outcomes in assisted reproduction treatments and an endometrial microbiota with low levels of lactobacilli.
More recently, a test known as EMMA has been developed. Using next-generation sequencing (NGS), it can assess whether lactobacillus levels are adequate and provide recommendations aimed at optimising the endometrial flora and, consequently, the conditions for embryo implantation.
The ALICE test, meanwhile, can detect pathogenic bacteria in the endometrium that may cause chronic endometritis — inflammation of the endometrial tissue associated with implantation failure.
Antibiotic treatment for this condition has been shown to help restore the endometrial microbiome and may improve pregnancy rates in these cases.
EMBRYONIC FACTORS
Regarding embryonic factors, current culture media and the availability of closed incubation systems allow embryos to develop under highly controlled conditions.
In general, the higher the embryo quality, the greater the probability of success.
However, in cases of implantation failure, screening for chromosomal abnormalities through preimplantation genetic testing for aneuploidy (PGT-A) may be recommended. PGT-A involves analysing embryos for aneuploidies using next-generation sequencing techniques.
IMMUNOLOGICAL FACTORS
With regard to immunological abnormalities, although some controversy remains, most scientific societies recommend screening for antiphospholipid syndrome and thrombophilias in cases of implantation failure.
The study of immune factors within the endometrium is an area in which much remains to be understood.
Immune cells present in the endometrium play a crucial role in implantation and the establishment of pregnancy. An appropriate balance must develop within the endometrium so that the embryo, which is genetically different from the mother, is not rejected and can successfully implant.
The precise mechanisms that enable this immunological tolerance are complex and continue to be investigated.
Several types of immune cells have been identified at the maternal–foetal interface, including uterine natural killer (uNK) cells, macrophages, T cells, dendritic cells and B cells. Their functions and concentrations vary throughout the different stages of pregnancy.
Using flow cytometry, it is possible to quantify these cells and assess the immunological balance, as well as establish recommendations when abnormalities are detected.
In particular, uNK cells play an important role in maternal–foetal tolerance. They account for a large proportion of the immune cells present in the endometrium at the implantation site.
Their membranes contain receptors known as KIR receptors, which bind to HLA-C molecules on the surface of the embryo. These molecules are involved in the immune system’s recognition of self and non-self.
Both KIR receptors and HLA-C molecules are polymorphic, and certain combinations may be less favourable. For this reason, studying them may be of interest in selected cases.
With regard to progesterone, we know that it is essential for adequate endometrial development, embryo implantation and the establishment of pregnancy.
There is growing evidence of the importance of maintaining appropriate progesterone levels in patients undergoing hormonal preparation for frozen embryo transfer, as well as in natural-cycle frozen embryo transfers.
Several studies have found that progesterone levels below approximately 9.2–10 ng/ml on the day before frozen embryo transfer are associated with lower pregnancy and live birth rates.
Ultimately, implantation failure remains a challenge in reproductive medicine. However, an individualised assessment of each patient, together with the availability of new diagnostic tools, can help identify possible contributing factors and determine the most appropriate treatment strategy for each case.
For this reason, at Clínica Fertia we have always been committed to personalised reproductive medicine, seeking a clear diagnosis and continuously working to improve our results in order to help our patients achieve their goal of building a family.
