Recurrent Implantation Failure

Uterine and endometrial factors affecting implantation

Introduction

Implantation is a process whereby the embryo attaches itself to the luminal surface of the endometrium (inner lining of the uterine cavity). This is followed by migration and invasion of the embryo into the deeper stromal layers (Figure 1). Traditionally, implantation has been considered as a process involving only the embryo and the endometrium, but recent studies show that even cumulus cell competency (cells around the egg) may also contribute to the process. While implantation is a process with a well-defined starting point, it is a gradual process which lasts for several weeks with no universal agreement on when the process is completed.

Implantation failure refers to the failure of the embryo to reach a stage when an intrauterine gestational sac is recognized by ultrasonography. From the clinical point of view, it is worthy to note that the term ‘implantation failure’ refers to two different types of situation, those in whom there has never been evidence of implantation (no detectable HCG production) and those who have evidence of implantation (detectable HCG production) but it did not proceed to beyond the formation of a gestational sac visible on ultrasonography. In this situation, it is clinically referred to as a biochemical pregnancy.

Recurrent implantation failure (RIF) is a clinical entity which refers to a situation when implantation has repeatedly failed to reach a stage recognizable by pelvic ultrasonography. There is as yet no universally accepted definition for RIF, despite many publications on this topic. Implantation failure may be a consequence of embryo or endometrial factors.

Embryo factors include the quality of the embryo/s, the number of embryos transferred, storage protocol/s in cases of frozen and thawed cycles and the stage of embryo development.

It is a matter of debate whether the diagnosis of RIF be based entirely on the number of embryos transferred or on the number of embryo transfer cycles. Many investigators prefer to base it on the failure to achieve a clinical pregnancy after three transfer cycles, whereas others propose to use the number of embryos transferred. There are pros and cons of each approach. The definition based on the number of embryos transferred is more scientific and logical, but the definition based on the number of transfer cycles is more pragmatic and easily understood by patients. At our facility, both factors are considered and a diagnosis of RIF is based on the transfer of at least 4 embryos in a minimum of three transfer cycles.

This article is aimed mainly at the endometrial or uterine factors affecting implantation.

Uterine factors

Congenital uterine anomalies

Congenital uterine anomalies may affect endometrial receptivity manifesting as either infertility or recurrent pregnancy loss.

The septate uterus is the most common structural uterine anomaly. It has long been recognized that uterine septae are associated with adverse reproductive outcomes such as first- and mid-trimester miscarriages but also possibly infertility. These poor outcomes are attributed not only to the disturbance of the uterine cavity but also to the inadequate blood supply to the septum. There is preliminary evidence that the septate uterus may also contribute to RIF. In a study involving women with a septate uterus undergoing IVF treatment, untreated septate uteri had a poor outcome following IVF treatment in comparison to women who had undergone hysteroscopicmetroplasty prior to IVF.

The same does not apply to bicornuate uteri, which rarely require surgical treatment. This is a relatively common anomaly and most women have no difficulty conceiving. The main risk for the woman with a bicornuate uterus is mid-trimester pregnancy loss and preterm birth.

Acquired intracavity conditions

A number of acquired intracavity uterine pathologies, including submucous fibroids, endometrial polyps and intrauterine adhesions, may contribute to RIF. The frequency of unrecognized intrauterine pathologies in patients with RIF varies between 25% and 50%.

Adenomyosis

There is literature evidence available to suggest that adenomyosis has an adverse effect on female fertility.

The prevalence of adenomyosis in women with RIF is likely to be underestimated as it may not always be detected by transvaginal ultrasonography. Magnetic resonance imaging provides superior soft tissue resolution and is probably the most accurate noninvasive diagnostic technique available.

Adenomyosis almost always affects the junctional zone of the uterus which is just beneath the endometrium and so may have a greater impact on implantation than intramural fibroids.

Hydrosalpinges

Hydrosalpinx is a Greek word meaning a Fallopian tube filled with water or fluid. It is now recognized that the live birth rate of patients with hydrosalpinges undergoing IVF is only one-half that of women who do not have hydrosalpinges.

The adverse impact of hydrosalpinges on implantation may be attributed to a direct embryotoxic effect, a mechanical effect whereby the accumulated fluid may flush the embryo out of the uterus, as well as a negative effect on endometrial receptivity. A study showed that the expression of leukaemia inhibitory factor, a cytokine essential for successful implantation, was reduced in the presence of hydrosalpinges, but the expression was restored to normal after salpingectomy. A further study showed that removal of hydrosalpinges may improve endometrial receptivity by restoring normal αvβ3 integrin expression.

Thin endometrium

RIF may sometimes be associated with a thin endometrium (<7 mm) noted at the time of ultrasound examination on the day of HCG administration or embryo transfer. The observation suggests that the endometrium is not optimally responding to oestrogenic stimulation. There are several possible underlying causes. It may be congenital, associated with Turner’s syndrome or a T-shape uterus. It may also be acquired, as a consequence of previous radiotherapy to the pelvis or iatrogenic damage to the endometrium following intrauterine surgery or infection. From time to time, the underlying cause may not be obvious.

In this particular clinical situation, hysteroscopic examination of the uterine cavity is recommended to rule out intrauterine adhesions or Asherman’s syndrome.

In the absence of any surgically correctable underlying pathology, there ought to be a strategy to improve endometrial growth by increasing the duration of oestrogenic priming prior to HCG trigger.

In women who fail to respond to the treatment outlined above or fail to achieve implantation again, our clinic’s policy is to repeat the treatment protocol in a further cycle, collect the oocytes, but not transfer any embryo. Luteal support should be started after oocyte retrieval as usual. An endometrial biopsy should then be obtained 7 days after oocyte retrieval for histological evaluation. If there is evidence of satisfactory secretory transformation, embryo transfer may proceed in a subsequent artificial cycle with high-dose oestrogen therapy. If, however, there is no evidence of secretory transformation, this suggests that the endometrium is unable to support implantation and the couple should be advised to consider surrogacy.

Endometrial scratch

Forty-five out of 134 subjects were randomized by consent to have repeated endometrial biopsy on days 8, 12, 21 and 26 of the cycle immediately before the IVF treatment cycle. They found that the treatment resulted in a significant improvement (approximately double) in the rates of implantation, clinical pregnancy and live births (27.7%, 66.7% and 48.9%, respectively), compared with control subjects who did not have endometrial biopsies (14.2%, 30.3% and 22.5%, respectively).

In Conclusion, in women with RIF, thorough investigations must be carried out to exclude any uterine pathology contributing to the clinical problem.

Couples with RIF should be reviewed by an experienced fertility specialist as there are inevitably many questions to be answered and important clinical decisions to be made. Patients need to be reassured that treatment is under the supervision of an experienced clinician. The couple should be offered ample time for their questions to be addressed and a clear treatment plan agreed. The appointment should not be just another ‘routine’ review. It ought to be a thorough review of the diagnosis of the underlying cause of infertility, the investigation results, the treatment protocol, the response to ovarian stimulation, the quality of the oocyte and embryos and possible explanation as to why they have not produced a successful pregnancy.

Appropriate counselling of the couple with RIF is of the utmost importance prior to proceeding with further treatment. The couple should be advised as to the likelihood of success in future cycles and advised not to pursue further treatment if their prognosis is poor (i.e. <5%).

– with thanks to Dr Cassim a Fertility Specialist from BioART fertility clinic