Reproductive Medicine - no proofs that endometrial scratch can improve implantation

Summary of the talk by Nicolas Zech at COGI 2015

(http://www.congressmed.com/cogichina/index.php/en/index.html)

To the present day, embryo implantation remains a black box and still represents the bottleneck of assisted reproduction.

In fact, human reproduction is characterized by a high prevalence of pre-implantation embryo loss of up to 75% and a high frequency of clinical miscarriages, suggested to exceed a rate of 10% of all clinical pregnancies. Besides the health and morphological potential of embryo(s) transferred, the receptivity of the endometrium is most crucial for successful implantation. The highly complex embryo-maternal dialogue orchestrating the implantation process is, despite of extensive research, still poorly understood. The timing of the implantation process is also important, as endometrial receptivity only exists during a relatively short period of time, the so-called ‘window of implantation’ (WOI).

Although the complex signal cascades of the embryonic-maternal cross-talk are far from being fully understood, several endocrine and autocrine factors have been already identified as key regulators. Trying to influence such complex regulation cascades, it was repeatedly reported that endometrial scratching might exert beneficial effects on the implantation of embryos in certain circumstances. However, taking a critical look at this topic, we have to question the quality of all yet published data. Parallels can be drawn to the reported effects of hCG on implantation. Our efforts to publish - to our best knowledge - the first randomized trial investigating the impact of intrauterine hCG administration prior to blastocyst transfer in relation to blastocyst morphology on a large study population including birth outcome as primary outcome in one of the high ranking journals failed even though all reviewers were in favor of publication. This reflects on the true quality of such journals and their influence on politics. Same most probably holds true for other publications and with other topics, much more then in former days. As we state in the hCG-manuscript: “Contradicting previous findings, the present study did not show any improvement of intrauterine hCG application in different settings. In fact, neither intrauterine hCG injection on day 3 nor on the day 5 had a beneficial effect on pregnancy rate (PR), delivery rate or implantation rate. This was true in transfers with top blastocysts and with non-top blastocysts as well.

Taking into account that IVF patients are a highly heterogeneous group with various medical histories and reasons for infertility, the numbers of patients analysed in the aforementioned studies were low. In most studies investigating the clinical impact of hCG, several types of stimulation protocols, IVF treatments, different types of transfers (fresh and frozen), as well as autologous and donor cycles were mixed. Additionally, and in contrast to our trial, transfers were mostly performed on day 3 before onset of the paternal genome and, no sub-analysis on embryo quality was done. In two of the cited studies, mean age of women was substantially younger as compared to our patient cohorts. Finally, all studies reported as final outcome clinical PR or ongoing PR, whereas our study also analysed birth outcome and late pregnancy loss. All these differences could substantially contribute to the controversial findings on a beneficial impact of hCG.

In summary, the majority of the aforementioned studies reporting a beneficial effect of hCG performed their analysis on small patient groups with even lower sample sizes in sub-groupings and thus are underpowered. Other weak points in the study conducts were early termination of randomized trial…or combinations of different transfer groups, mixtures of donor- and non-donor cycles, or lacking information in regard of the studied population and embryo quality, thus lowering the validity of the analysis performed. The high number of IVF cycles with failed implantation - despite of transferring apparently morphological good and viable embryos- has led to the adoption of adjuvant therapies with the aim to improve endometrial receptivity and implantation rates. However, it has to keep in mind that beside all the enthusiasm the molecular background of implantation process remains a complex issue and intervention therapies are obviously not as simple as often suggested”.

Thus, before starting to discuss possible beneficial effects of endometrial scratching, but also of other “fancy” technologies which are considered to improve the IVF outcome, let`s try to be on the same page and not to believe in published data in an un-reflected manner, even though  they might be published in “high-ranking journals”. Don`t believe everything that is published, question results before believing – the more so, the higher a journal is ranked. Sad but true!

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