Clinical aspects in monitoring performance of the IVF lab

If you bring to your mind the moments you check on beta-hCG results and pregnancy rates is not hard to see that this is where clinicians and embryologists hit common ground.

Checking on pregnancy rates of your ivf unit is not only part of quality management, is what both clinicians and embryologists identify with, something that both of can easily get hooked on, as we try to check out how our cases do, whether results are anticipated or not and whether they truly reflect our practice.

At the core of ART practice lies the laboratory. As results of ART treatments remain moderate despite advances in the field, there is a constant strive to improve efficacy. But as processes are being added on and new protocols are being introduced, there is a necessity to objectively monitor the outcomes of our practice, and this is where key performance indexes (kPIs) are coming in to tell us how we are performing (1).

Monitoring performance of the lab includes kPIs for many diverse parameters, as in structure, processes and outcome-related kPIs. And although both structure and process-related kPIs are essential in the effort to achieve, it is the outcome-related kPIs that reflect on overall effectiveness of care, and particularly where the interaction lies with clinical factors.

Lab outcomes kPIs can be either intermediate, including markers suggested by the Vienna and Alpha consensus, or they can be end-result kPIs, that is implantation rates, as well as clinical pregnancy and live birth rates. Intermediate outcomes reflect laboratory practice, while in end-result kPIs we can recognise the clinical factors of endometrial receptivity as well as patients profile  (2).

So, how is this interaction with clinical factors taking place and what does it involve for the lab? Well, first we can identify clinical factors that may have an impact on lab outcomes by various ways, either due to the population being treated, or due to the medical procedures involved. Then, if we examine the opposite way, looking at lab performance through kPIs, we can see how this may have an impact on clinical decision making and clinical practice. If we are to continuously improve our practice we need to recognise this complex interaction and communicate it, so that interaction becomes constructive for our IVF team. Ultimately, essential aspects of lab performance through a clinical perspective will then provide the basis for patients counseling.

Looking at the clinical factors and their impact on lab outcomes we can make use of the 3Ps rule that stands for population, protocol and procedure. Following such a mnemonic helps with standardising information both for gametes and  endometrial receptivity. The population refers to characteristics of patients being treated, medical conditions and diagnoses relevant to infertility, while stimulation protocols and medical procedures refer to medical treatment, from ovarian stimulation to oocyte pick-up and embryo transfer.

The way clinical factors interact with the IVF lab outcomes is as follows: 1. by affecting quantity of gametes, 2. by affecting quality of gametes, or 3.  by affecting endometrial receptivity. While quality of gametes and endometrial receptivity are self-evident it is the number of oocytes that is critical for lab performance, as the more oocytes retrieved, the more embryos, the more blastocysts and the higher the implantation and live birth rates (3, 4).

To start with, it’s important to relate outcomes to the population treated. Female age remains the most critical factor affecting both quantity and quality of oocytes that reach the lab, whereas women with low ovarian reserve, as shown by low AMH levels, have a similar impact on numbers, regardless of age (5, 6). The diagnosis of polycystic ovaries and polycystic ovarian syndrome, on the other hand, maybe related to a high yield of oocytes, however, quality is often impaired as the number of mature oocytes that reach the lab can be compromised (7). Women with endometriosis commonly present with oocyte quality issues, while in advanced stages and in the presence of endometriomas oocyte numbers can also be affected (8).

Certain gynaecological conditions are associated with lower implantation rates, such as cases with thin endometria, where despite oestrogen-based protocols and several add-ons, endometrial development remains poor (9). Other gynaecological conditions that have been associated with reduced endometrial receptivity include adenomyosis and the presence of uterine leiomyomas, some of which, depending on location and size may have a negative impact on implantation (10). More recently, research has focused on chronic endometritis, which appears to be more common in unexplained infertility and recurrent implantation failure. In all the above cases, the lab maybe creating good quality embryos, but implantation maybe compromised due to impaired receptivity.

The choice of protocol plays a certain role as well. Although, currently the short GnRH-a antagonist ovarian stimulation protocols is in wide use, as it has been shown to be both effective and safe, the long GnRH-a agonist protocol is still indicated in endometriosis patients as pregnancy rates are reported higher (11), also when the few extra oocytes are important for the lab as in cases of PGT, or testicular biopsies in TESE cases.

The selection of gonadotrophin in ovarian stimulation is a matter of ongoing debate. There is increasing evidence of the role of LH in both oocyte quality and quantity, particularly in women of advanced age, as well as in poor or suboptimal responders (12). Addition of LH in ovarian stimulation protocols has been associated with improved ovarian response in the above groups, whereas clinical pregnancy rates appear to be improved as well (13).

Regarding the role of final triggering in ovarian stimulation, it has been suggested that the addition of GnRH-agonist to recombinant-hCG, as in dual trigger, maybe more beneficial, especially in cases with a history of immature oocytes in previous cycles (14). In the same context, the time interval between administration of the final trigger and oocyte pick-up maybe important to allow for final oocyte maturation, as in some cases of PCO for example.

Next, it is important to examine the interaction of medical procedures and their impact on the IVF lab performance. The procedure of oocyte retrieval can affect the oocytes that reach the lab, so  operator experience is a crucial factor, as the number of oocytes retrieved relates to level of experience, even more so in cases of poor response, or difficult ovarian access. The use of equipment is also important, the suction applied to retrieve oocytes is to be used with caution;  excessive pressure and turbulence within the follicle should be avoided in order to minimise damage to the oocyte (15).

The procedure of embryotransfer is the most critical process in the sequential events of an IVF cycle. A good embryotransfer can maximise embryo implantation, while a poor one will inevitably compromise results, regardless of embryo quality and endometrial receptivity. The transfer has to be smooth, easy and with minimal if any discomfort to the patient to avoid uterine contractions. The presence of blood in the transfer catheter and the cervical os has been associated with decreased implantation (16). Operator experience, again, is of great impact, while a mock embryotransfer beforehand is strongly suggested in all cases to define cervical anatomy and schedule, where necessary for cervical dilatation.

We can now assess the other side of interaction, that is how lab performance affects clinical decision making and clinical practice. Initially, blastocyst transfers have prevailed in many IVF units as synchronicity with the endometrium is better and implantation is higher at least in good prognosis patients, where the objective is transfer a single embryo (17). A policy of single embryo transfer is generally accepted as the most effective strategy to minimise multiple pregnancies and associated morbidity, so embryo selection at the blastocyst stage is a crucial point. Last, a good blastulation rate allows for a good number of blastocysts to biopsy on PGT programs, where timing of biopsy has shifted from cleavage stage to blastocyst stage.

With the advent of cryopreservation clinical practice in infertility care has changed dramatically. Cryopreservation performance in the lab is a crucial factor in planning and defining medical protocols, both in terms of patients safety and protocol efficacy. The introduction of vitrification has facilitated cycle segmentation where the risk for OHSS is high or where endometrial receptivity is impaired as in hyperoestrogenemia, in thin endometria, or the presence of endometrial polyps. In a similar context, effective cryopreservation of embryos has facilitated embryo banking which now stands as an effective strategy in poor responders, where implantation is improved by accumulating embryos from consecutive cycles. Last, an effective cryopreservation program is the starting point for the implementation of fertility preservation programs, so survival rates, especially in oocyte vitrification protocols, are important for patient counseling and choice of medical treatment.

It is clear that the interaction between clinicians and the ivf lab affects the overall performance of the ART program, hence the need to communicate performance on a regular basis. Meetings with clinicians and embryologists provide an opportunity to discuss performance and kPIs, clinical, embryological and overall performance indexes. It is also an opportunity to discuss performance of certain cases of interest where implantation did not occur, and revisit the stimulation protocol, procedures of oocyte retrieval and embryo transfer,  lab information that we have on oocytes, on sperm and embryos. In this context, reexamining prognosis for such incoming cases provides a tool to explain  treatment outcome.

Also, kPIs per operator can be highlighted either in the context of oocyte retrieval or embryotransfer but also in the setting of fertilization and other lab-related procedures. Pregnancy rates per operator per defined area of activity is the way to identify deviations from the average. Last, regular meetings provide also the opportunity to review current practice and discuss the introduction of new protocols and new procedures. Before routines are changed and new data come in it is critical that all parties involved are informed and kPIs monitored with attention.

Finally, when clinicians get to communicate lab performance in the context of the overall performance of the IVF unit to patients, it is important to provide informative counseling and enable patients to reach valid decisions. In this context, it has been suggested that counseling should also be focusing on cancellation rates, either due to clinical or embryological reasons, an important piece of information for all cycles, but in particular for natural cycles, poor responders and PGT cycles. Last, a specific mention should be made on the chance of supernumerary embryos, an indicator reflecting both clinical and lab efficiency, with clear implications on cumulative pregnancies and live births (18).

In summary, clinicians and embryologists interact in a complex way affecting one another through their standardised procedures, always in relation to the population treated. Recognising this interaction and communicating its critical aspects in a structured way will make overall performance of the IVF unit both, more efficient and ultimately more effective.

©2021, Nicholas Christoforidis, Fertility Matters
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