Recurrent Implantation Failure (RIF)
In order for a pregnancy to occur, a blastocyst—a 5-7 day old embryo in the form of a rapidly dividing ball of cells—must implant into the innermost uterine lining or endometrium, the success of which depends on a number of factors. Recurrent implantation failure (RIF) is the inability to achieve implantation or an ongoing pregnancy from in vitro fertilization (IVF) after multiple embryo transfers. Patients who find themselves in this position are often desperate for answers. IVF is an arduous process, and it’s discouraging to make it as far as the embryo transfer but not to a healthy pregnancy. Fertility doctors generally focus on two factors to determine the cause of implantation failure.
First is the quality of the embryo. You can read about embryo grading and genetic screening in our full courses on the subject. Second, fertility doctors will look at the uterus itself. This will likely include a physical exam for the presence of fibroids or other endometrial abnormalities. The doctor will likely also consider the role of endometrial receptivity, which affects the timing of the transfer, however objective analysis of the endometrium with definitive determination of its receptivity remains elusive.
Role of the Endometrium in Implantation
Embryo implantation is a complex and highly coordinated process, and in order for this to successfully occur, the endometrium must undergo considerable changes in synchrony with the implanting embryo. The uterus is only “receptive” to an embryo implanting for a short period of time known as the “window of implantation.” Some studies suggest that endometrial receptivity and embryo-endometrium communication is so critical that two thirds of implantation failures may be due to defects in this stage alone, underscoring why predicting the optimal time frame is of considerable interest to clinicians.
Assessment of Endometrial Receptivity
Several methods are employed to estimate the receptivity of the uterus before embryo transfer, but each comes with its own shortcomings and no method has proven to be reliably predictive. For example, histological assessment—using a microscope to analyze a biopsy of endometrial tissue—had been used to predict implantation receptivity for decades but was eventually shown to be unreliable in the face of randomized studies. Transvaginal ultrasound is among the most commonly used methods to assess parameters known to impact receptivity such as endometrial thickness, volume, contractility, and blood flow. Although ultrasound methods are limited in value and accuracy, they have proven to be more useful in estimating the window of implantation than other methods such as blood and uterine fluid biomarker testing.
Endometrial Receptivity Array (ERA)
Recent advancements in transcriptomics—the study of gene expression—has facilitated the development of gene expression profiles of the endometrium during its various stages of development. The endometrial receptivity array (ERA) is a molecular diagnostic test that analyzes gene expression patterns during different phases of the menstrual cycle in an endometrial tissue sample obtained via biopsy. This is a fairly invasive procedure, generally performed when the patient is awake. At a minimum, it’s “uncomfortable” though many patients describe the pain as far more intense. Receptivity is then assessed by comparing results against a database of known receptive and nonreceptive endometrial profiles. If the endometrium is found to be non-receptive, the test will determine at what time receptivity will occur, allowing a future transfer to be performed during this window.
Cost of the ERA Test
In the United States, the biopsy itself averages $200 and the test is approximately $600-$1000. Neither is typically billed to insurance so patients will have to foot the cost themselves. Similarly, in Brazil and Japan, an ERA test will set you back around the equivalent in local currency: approximately R$5,000 and ¥118,000 respectively.
Clinical Data on ERA Effectiveness
Patients Who Have Yet to Have a Failed Transfer
The first adequately powered randomized controlled trial of ERA-guided receptivity-timed transfers was published by Doyle et al. in December 2022 and has poured cold water on the notion that the ERA test is of much value in predicting the window of implantation. The study compared live births from single euploid (genetically normal, as determined by PGT-A screening) frozen embryo transfers in ERA-guided vs. standardized transfers. Participants who did not have euploid blastocysts were excluded. 767 participants were included in the study and the mean age was 35 years. The study was double-blinded meaning that neither the participants nor the investigators knew which treatment the study subjects were receiving and the participants were randomly assigned to their treatment groups.
All control group participants and those intervention group participants with receptive ERA results received frozen embryo transfer at the standard timing of 123 ± 3 hours after the start of progesterone, while the intervention group participants with nonreceptive ERA results underwent frozen embryo transfer based on the recommended timing from the endometrial receptivity results as shown in the table below.
The primary outcome was live birth. Secondary outcomes included clinical pregnancy, biochemical pregnancy, chemical pregnancy, and ongoing pregnancy. The data showed that there were no significant differences between groups for any of the outcomes. The table below shows the results of the primary outcome (live births) and one secondary outcome (clinical pregnancy) for all patients.
Further subgroup analyses showed that there were no statistically significant differences between patients who were deemed nonreceptive by ERA testing across groups as shown in the table below.
Taken together, the data from this double-blind, randomized, controlled trial show that endometrial receptivity testing provided no significant advantage in live birth rates—or any other positive clinical outcome—compared with standard timing for frozen embryo transfer with PGT-A tested euploid embryos.
Patients Who Have Experienced a Previous Failed Transfer
For patients who have had a previous embryo transfer that has failed, the data also indicate that ERA is not helpful in improving outcomes. That said, embryo transfers can fail for a variety of reasons, and despite the conclusions outlined below, proponents of ERA argue it has yet to be proven ineffective for those suffering from recurrent implantation failure (RIF), whereby on multiple occasions transfers failed because embryos did not successfully embed in the endometrium.
Alternative Treatments for Recurrent Implantation Failure
Platelet-Rich Plasma (PRP)
Plasma is the fluid component of blood, while platelets are cellular fragments found in the blood that are enriched in growth and healing factors with antimicrobial and anti-inflammatory properties. One of the functions of platelets is to promote tissue healing and growth when transported in the blood towards sites of injury. Platelets can be concentrated from whole blood into the form of platelet-rich plasma (PRP) and delivered to the site of needed tissue repair.
Several clinical trials have shown promise in intrauterine PRP infusion with significant improvements in clinical pregnancy rate and several other measured parameters, including endometrial thickness, implantation rate, and live birth rate. Although a full mechanistic understanding of PRP in treating RIF remains to be determined and more research is needed to determine timing and dosage, it remains a promising potential treatment.
Granulocyte Colony-Stimulating Factor (G-CSF)
G-CSF is a molecule that stimulates the production and release of granulocytes (a type of white blood cell that helps the body fight infections) and stem cells from the bone marrow into the bloodstream. There is some evidence that administration of G-CSF in the form of Neupogen® has positive effects on endometrial receptivity, but one randomized study showed no effect while other studies showed limited, but still promising, effects.