Combined contribution of zona bound sperm selection together with microinsemination without penetrating the oocyte membrane, a cost-beneficial approach to increase cycle’s efficiency?

Although it is difficult to estimate given the absence of a clear and global consensus on the way in which the results of assisted reproduction treatments should be measured, it seems obvious that these still have room for improvement, provided that several attempts are often necessary in patients or couples to achieve parenthood/maternity.

We can understand by “attempts” different concepts as any repeated ovarian stimulation treatment and follicular aspiration to obtain oocytes, or classic in vitro fertilization (IVF) procedures/microinjections, or even repeated transfers of viable embryos, and this notion has been recently used to measure reproductive outcomes in a different way by using cumulative probabilities on the whole insemination products, including to evaluate sperm selection methods (1).

Of all the processes that assisted reproduction treatments consist of, to simplify, diagnosis, ovarian stimulation, obtaining mature oocytes, fertilization with prepared sperm, embryo culture, and embryo selection to prioritize among those available the ones to be transferred, the one that offers us the greatest number of possibilities is undoubtedly the selection of the few spermatozoa that will be either closely deposited besides the oocyte expecting them to do the job or mechanically inserted to fertilize it, to then being converted into a competent embryo able to implant and develop until a child is born.

In each ejaculate, their number can vary from a few spermatozoa to hundreds of millions; however, in almost all cases when there are some found, they by far exceed the number of oocytes available for insemination (2).

These processes of sperm selection of a tiny amount and discarding many have historically been performed either by methods of self-selection on the basis of motility properties with the use of density gradients or swim-up procedures or by the decisions of the embryologist in charge also on the basis of motility and shape or in some cases aided by pre–sperm characterization or selection techniques such as magnetic activated cell sorting of nonapoptotic spermatozoa, intracytoplasmic morphologically selected sperm injection, microfluidics, birefringence, zeta potential, physiological intracytoplasmic sperm injection (ICSI), or the most recent artificial intelligence–based methods that, from the point of view of cost-effectiveness and the quality of the evidence supporting their use, are still in doubt or limited to very specific cases.

What is certain, and what seems to be accepted by the scientific community in our area, is that given the genetic and biochemical individuality of the spermatozoa, their excessive number, and the technical simplicity of their obtention and manipulation, there is a growing interest in characterizing the spermatozoa that will result in embryos of higher quality and possibilities of becoming healthy newborns and developing techniques that can identify, select, and use them subsequently, thus contributing to increasing the reproductive possibilities for each try, whatever the denominator of the analysis may be: per patient; stimulation initiated; puncture; act of fertilization with IVF or ICSI; or embryo transfer.

This improvement will impact by getting more and better embryos per inseminated oocyte, fact that may be of particular interest on cases with low response and scarce oocytes available to use but ideally useful for all.

In the article by Hatakeyama et al (3), the selection of the most suitable sperm is based on using sperm bound to the zona pellucida, whereas the microinsemination method is performed by sperm fusion (assisted sperm fusion insemination), without penetrating the oocyte membrane, compared with conventional ICSI.

Although results seem very promising, caution is commended, and more research is needed to further address this question, before being truly sure that this combination of techniques could enhance a patient’s opportunities.

First, because the lack of knowledge about the reasons behind the reported improvement, as 2 differences can be stated between the compared groups: controls’ sperm selection performed by the embryologist and conventional ICSI vs. those on the intervention group, selecting those zonas bound sperm and then using assisted sperm fusion insemination. This design does not allow to discern whether either the microinsemination method or sperm selection method is responsible for such proven improvement. Perhaps selecting zona bound sperm provides a natural selection method from which we can take advantage to improve outcomes, or perhaps the gentle insemination method without needing to cross the plasma membrane is responsible for these observed outcomes. A combination of both contributions cannot be discarded; however, further research is needed to disentangle this.

Second, their sibling oocyte design reduces interindividual variability, to some extent controlling potential confounders related to the patient’s characteristics, permitting valid comparisons on fertilization and embryo development/quality, but limits the possibility to compare the most relevant reproductive outcomes per embryo transfer or the most informative cumulative first live birth rates per cohort.

The approximately 20% higher fertilization rates and the usable embryo rate that improved in the experimental group from 28.1% to 45.8% provide interesting data supporting further research and characterization of this method in future works with an appropriate sample size to determine how these are converted into more meaningful improvements on first live births obtained per fertilization process, using cumulative rates, not only the first embryo transfer rates.

One can expect these improvements related not with the selection methods but mainly on the insemination technique because the intermediate outcome of the degeneration rate is significantly lower on the experimental group, pointing to the hypothesis that the excess of embryos obtained is mainly through avoiding to some extent the harm potentially induced by classic ICSI on their cases.

Their baseline degeneration rate of 8.8% seems comparable to those described as ideal recommended by some consensus published on the topic (4), from 10% sat most as the competency value and a benchmark of presenting ideally 5%, meaning that in fact, their numbers are down to the range of fairly good degeneration rates, as they were decreased down to 0, even better than what was recently reported by the use of modern piezo-ICSI techniques, of 6.3% (5).

Nevertheless, in today’s busy IVF units, a careful analysis of the workload added by using these new procedures, compared with the standard ones, may bring light to the real usefulness of this method and the possibility to spread across laboratories worldwide.

Furthermore, this study has been limited to cases without presenting severe oligospermia, 1 of the groups candidates to undergo ICSI treatment, that deserve also to be explored.

Additionally, this technique seems subordinated to the availability of immature and degenerated oocytes available from each aspiration, which may limit the possibility to treat all patients.

Further reflections from the investigators on these queries could help readers to precisely understand the relevance of their findings for a clinical setting.

In conclusion, developments have been shown in a potentially interesting field of research that need to be further explored but that point to one of the probably most underrated contributive fields of assisted reproduction that we have the obligation to assess and improve.

Declaration of Interests

N.G. has nothing to disclose.