Since their emergence in the late 1970s, reproductive medicine and assisted reproductive technologies (ARTs) have provided a beacon of hope for millions worldwide grappling with infertility and normalising parenthood for same-sex couples in certain regions.

Despite varying success rates influenced by factors such as age and underlying fertility issues, the overall trajectory of in vitro fertilization (IVF) outcomes has been positive, with more couples realising their dream of starting a family through advancing ARTs.

In their bid to optimise best practices, the global IVF profession continues to strive to implement a single embryo transfer model, whilst maximising the chance of a successful pregnancy in a shorter time frame with less uncertainty.  Vitrification and improved embryo selection through enhanced quality control, time-lapse monitoring, PGT and most recently the introduction of AI for selecting superlative embryos for transfer is undoubtedly having a positive impact on clinical outcomes. But it can be argued the focus on preferential selection of specific embryos is a double-edged sword, and it comes at a price.

Because much of the additional processing required to produce (or reveal) the best embryos is currently not automated, the time and resource required to elevate success rates has increased dramatically.  The rapid introduction of time critical biopsy for PGT in combination with vitrification, for example, has significantly increased the workload of the embryologist and, unless the size of the embryology team is increased to cope with this extra assignment of tasks, significant levels of risk are immediately introduced into an already overburdened and under resourced system.

These are risks that were not there before, compounded by the fact that increased levels of success continue to increase the demand for specialised fertility treatments.  And because these activities require the knowledge, skill and dexterity of highly trained embryologists, the extra resource may not even be available to safely supply the increased demand for fertility treatment.

For example, the number of witnessing steps required in a cycle of ICSI has almost doubled since the introduction of biopsy for PGT because it is no longer sufficient to simply identify the patient at the point of moving material form one receptacle to another. It has now become essential to verify that the correctly numbered gametes, embryos, or cells are checked within multiple processes to guarantee the cells in a numbered PCR tube were derived from an embryo stored in the same numbered vitrification device for example.

The analyses itself also creates further opportunities for error because when characteristics that potentially determine the outcome of a specific embryo or that rank embryos within a cohort in order of priority for transfer, this knowledge can’t be overlooked. Especially if transferring a sub-optimal embryo is either unlikely to lead to a live birth or lead to a genetic disorder.  This places a huge burden of responsibility and accountability on individual members of the embryology team to not only ensure the right patient is selected but also the right embryo, because the consequences of making a mistake could be catastrophic.  Errors in healthcare lead to personal tragedy, reputational damage, complex litigation and financial expense.

Authors such as Tochi Amagwula  have recognised that, “facilities offering PGD services expose themselves to a new realm of liability in which damage awards can easily exceed the limits of a facility’s insurance policy”.

The additional work burden, coupled with the new tier of accountability can potentially exacerbate human factors like stress, pressure, fatigue, and complacency creating yet further opportunities contributing to errors. The esteemed author, Murat Basar, describes an ‘unseen crises, where high stakes decision making, emotional burden, long hours and workload leads to burnout, depression and anxiety. The author Basar suggests that addressing the factors contributing to burnout and highlighting the importance of addressing mental health and work-life balance in reproductive medicine, may ultimately lead to even greater improved success rates in IVF.

In addition to the better-known human factors, the phenomenon of normalisation or deviance or ‘norms’, sometimes referred to in IVF as ‘involuntary automaticity’, means that repetitive mundane tasks (like tubing countless biopsies for PGT) can lead even the most conscientious and skilled professional to become distracted, overlook hazards, neglect safety procedures and underestimate risks. Individuals can’t be ‘blamed’ for this failing because it is well documented to be a condition of the human psyche. However, it is important that quality managers and Lab directors recognise the risks their staff are exposed to in order for them be encouraged to implement safeguarding measures.

Humans will, and often do make mistakes. One doesn’t have to look very far for many examples of mistakes occurring in IVF.  And it stands to reason that the incidence of error increase as a result of introducing increasingly time consuming and complex methods into a process, unless adequate control measures are implemented to mitigate the associated risks. There are already numerous reports of serious adverse events in relation to PGT emerging, like the case of one California fertility centre who accidentally transferred an embryo with a rare mutation in the CDH1 gene because “they simply read the report wrong”.

A recent study of large data, conducted by an MSc student on the University of Leeds CEART programme suggested the true rate of error related to misidentification to be close to 0.3% of all procedures performed. If deemed to be true, this figure is significantly higher compared to similar studies that don’t necessarily take all events, including corrected mistakes, into account.

Of course, one is not suggesting that it is better off not knowing the embryo’s qualities and genetic characteristics, because, depending on your viewpoint, the benefits to the patients outweigh the risks. Many practitioners share the view of Capalbo, who believes “choosing the best embryo to transfer is crucial, especially when a single embryo transfer program is adopted for different clinical reasons”.  However, it does highlight the importance of verifying the selected fate of an embryo in a fertility center’s cryostore and shines a spotlight on reliable embryo level witnessing and cryogovernance.  It also emphasises the need for enhanced witnessing in a process like biopsy for PGT, vitrification and thaw/biopsy/refreeze (TBR) that now command gamete and embryo level witnessing.

It is something that genetics companies are concerned about too.  So much so that there are already active collaborations underway to integrate genomic bioinformatics systems with labelling and witnessing systems to track, trace and electronically witness the processes both upstream and downstream of the cryopreservation of biopsied embryos.

And this is where barcodes can play a crucial role. Especially because barcodes are designed to be globally unique identifiers for products, which means every individual culture well, biopsy dish, PCR tube and vitrification device can be labelled and matched with a globally unique identifier in advance of the movement or transfer of a gamete, embryo or biopsy.

This is possible because barcodes are Globally unique, not only to the patient but even down to the individually numbered gametes, embryos and biopsies. This means that groups of correspondingly numbered labels can be utilised to verify correctly numbered gametes and embryos through a process like biopsy, vitrification or thaw/biopsy/re-freeze (TBR).

For example, using the Matcher system, a uniquely numbered culture well in a petri dish can now be barcoded and matched to correspondingly numbered biopsy dishes and PCR tubes.  The same embryos can then be matched to their correspondingly numbered vitirification device.  Although biopsy and vitrification are two separate processes, through the use of barcodes, a chain of custody can now be generated that guarantees the cells in the numbered PCR tube destined for PGT are from the same numbered device containing the cryopreserved embryo in storage.

And when the PGT results are known and attributed to the specific embryos in storage, informed decisions can be made about intended fate of specific embryos for transfer or disposal. Scanning the barcode on selected gametes and embryos provides confirmation before the embryos are finally removed to verify the right embryo was transferred to the right patient, or that the correct embryos were disposed of safely.  Even inferior quality, aneuploid or mosaic embryos that remain in long term storage for posterity can be flagged as ‘not for use’. When these embryos are scanned prior to warming, a clear audiovisual alarm will alert the embryologist of their status to avoid accidentally warming and transferring the wrong embryo.

It’s not only important to trap, prevent and mitigate errors of transfer, but equally important to have the physical evidence that proves there were no errors in the process leading up to the cryopreservation and subsequently, when embryos were thawed for transfer.  And this includes photographic evidence, because benchtop and pocket Matcher devices also offer the advantage of capturing and recording an image of the items scanned in real time, at the point of use.

Verifying that gametes and embryos were moved into the correct storage location is also important for enhanced cryogovernance, and this is only possible if globally unique machine-readable identifiers, like the barcode, are assigned to these items to facilitate a link between the real physical world managed by humans, and the virtual digital world managed by computers.

Traceability is not just important, it’s a vital core component of every fertility center’s total quality management system for a whole variety of reasons. A fertility center simply could not function and would not last for very long without adequate traceability systems in place.

And in terms of quality control you can now categorically prove the 5 R’s. Right patient and embryo, Right Time, Right Place, Right Process and of course, Right Product.  This is what we really want to prove.

And this ultimately leads to best practice. For example, it’s important for helping to drive efficiencies which leads to improved outcomes and results.  It’s important for ensuring patient and staff safety, quality control, regulatory compliance and efficiency of the healthcare system, and probably most importantly, if implemented correctly it can even mitigate the risks of error and prevent mistakes.

To see Matt discuss this topic with Chelsey Leisinger, VP Lab Compliance for CCRM Fertility have a look at their video