Recurrent implantation failure (RIF) occurs when an individual with good quality embryos has at least three failed attempts at embryo transfer during an IVF cycle1,2. Despite the advances in fertility treatment technology, RIF is still a hurdle for those trying to conceive.
The successful implantation of an embryo is not unlike a farmer growing their crop! To grow a healthy and bountiful harvest, a farmer must consider three important factors: the quality of their seeds, the soil and the environment. Like the farmer must ensure that he is using the best seeds to produce his crop, an IVF doctor must ensure that the embryos are of the highest quality. A farmer must prepare their soil for planting by plowing and fertilizing it, just like how a uterine lining (endometrium) must be prepared through hormone treatments to produce a suitable implantation area. Lastly, even if the best quality seeds and soil are used, environmental factors such as the weather or pests can affect a farmer’s harvest. This is similar to how other factors in our body, such as diet, exercise and stress, can impact implantation despite having good quality embryos and a well-prepared uterine lining.
If any of the above three factors are incomplete, it may result in failure of a seed to germinate– or the failure of an embryo to implant!
Even in natural cycles, implantation is not a guaranteed process. In fact, for otherwise healthy young couples using timed intercourse, the implantation rate is approximately 20-25% per cycle3. IVF produces similar implantation rates, around 25%3.
Which factors can impact uterine receptivity in RIF?
Many different factors can influence uterine receptivity. The following are three common conditions resulting in an increased risk of implantation failure:
- Uterine anatomical issues may interfere with implantation. Sometimes individuals are born with atypical formations (such as a septate or bicornuate uterus) or can develop them throughout life (uterine fibroids, hydrosalpinx, endometrial polyps, etc.)3 that physically interfere with the implantation process.
- Blood flow to the endometrium and placenta is crucial to transfer nutrients to a developing embryo. Conditions that interrupt this blood flow, such as blood clots, can contribute to implantation failure or miscarriage3.
- Lastly, an endometrium must be an ideal thickness to receive and provide nutrients for a developing embryo. The ideal implantation thickness is usually between 7-8mm, with a trilaminar or “three-layered” appearance3. The endometrium must also effectively communicate with the embryo to enable implantation. A thin or unresponsive endometrium can be due to age, medications, estrogen deficiency or previous trauma to the endometrium4. While part of a typical fertility treatment regimen involves hormonal supplementation to thicken the endometrium, complications of the embryo-endometrium interaction may persist, resulting in a failed implantation.
How can uterine receptivity be assessed and diagnosed?
When faced with recurrent implantation failure, the first step in improving receptivity involves determining an ideal implantation window. This refers to the period of time in the cycle where the uterine lining is most receptive. In this window, the chance of implantation is at its highest.
A test called an Endometrial Receptivity Array (ERA) is one of the most common tests to assess receptivity. This test, developed by researchers, analyzes over 200 genes involved in uterine receptivity4. This result of this test not only provides info on whether a uterus is receptive or unreceptive but also determines an ideal window of implantation for that individual4.
This ERA sample is collected through an endometrial biopsy and is typically performed during a “mock cycle” on the exact day an embryo transfer would have occurred. This way, the results of the ERA will determine how receptive the uterus would have been if a transfer had occurred. If the ERA predicts the uterus to be receptive, the same timing can be used for future embryo transfers. If it is found to be unreceptive, the window of implantation is shifted using progesterone administration and the ERA is repeated in the following cycle.
How is RIF treated?
In cases of RIF, a comprehensive evaluation by your fertility clinic must be performed to uncover which factors contribute to the implantation failure. Treatments for individuals experiencing RIF may include surgical procedures, hormonal supplementation, blood-thinning medication, and other interventions.
Examples of common procedures include endometrial scratching, where a catheter is inserted through the cervix and the uterine lining is “scratched” prior to embryo transfer5. While this may sound counterintuitive, this scratching stimulates the endometrium, and the resulting low-level inflammation appears to actually enhance implantation of the embryo5! If using a certain type of catheter equipped with a biopsy needle, called a Pipelle, a small sample of the endometrium can be taken at the same time to assess the quality of the endometrium itself5.
Another common procedure involves the use of a technique known as assisted hatching. A developing embryo is enveloped in a hard “shell” called the zona pellucida. Around day 4 of development, this shell cracks open and the embryo emerges in a process called “hatching”. Only a hatched embryo is capable of implanting in the endometrium, so an embryo that fails to hatch will result in a failed implantation. During IVF, after an egg is fertilized and has developed for a few days, an embryologist can create a small tear in the zona pellucida to help the hatching process! (Learn more about assisted hatching in our article on the topic here!)
Your fertility physician can use information from your medical/reproductive history, genetic testing, blood testing, sperm analysis and diagnostic imaging to develop a personalized treatment regimen for each individual experiencing RIF.
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