Thank you to CooperSurgical® for inviting me to talk to you about our PICSI implementation plan today. So PICSI is a treatment add-on that we are hoping to offer our patients very shortly, so hopefully in the next month or so. We are going to offer it to both NHS and private patients. But it will be a self-funded treatment option. So NHS patients will have to pay. I’m just going to talk you through why we want to offer PICSI to our patients and what our approach to implementing it in the lab is. I’ve got no conflicts of interest to declare.

First of all, and why do we want to offer PICSI? We are very much an evidence-based clinic. If there is evidence to support the clinical use of a treatment add-on, then we do want to offer it to our patients. But with many treatment add-ons, the evidence is very limited or lacking. Some treatment add-ons, they will benefit a certain group of patients. Being able to identify that group of patients so that we don’t over prescribe can be difficult. The first thing that we did was a literature review to look at the evidence and see if it did support the clinical use of PICSI and if so, in which patients it would benefit the most. I’m not going to go through the whole literature because there is a massive amount, but I do want to focus on the largest trial to date, which is the HAB Select trial.

Hopefully most of you will have heard about it, but basically this was a large multicenter, randomized, controlled trial that looked at randomized 2,700 couples to receive either PICSI or standard ICSI. The primary outcome of the trial was term live birth rate, which didn’t differ significantly between the two groups. They did also look at secondary outcomes and the only significant one was miscarriage, which was significantly lower in the PICSI group at 4.3% vs 7% in the standard ICSI group.

As the authors of the paper have pointed out, that data is presented per person randomized and you can’t miscarry if you aren’t pregnant. So if you actually look at the data per clinical pregnancy, the difference is much greater. It’s 12.3% in the PICSI group and 19.6% in the ICSI group. That suggests that PICSI could reduce the risk in miscarriage by around 37%. But because this was a secondary outcome, it was argued that it was a chance finding. So that is something that they did explore as they moved into the mechanistic arm of their trial, and as part of the mechanism arm, they built a predictive model.

What they did is they took the data from the trial and aggregated it into 10 year intervals for female and male age. I’m going to talk to you about that data today, because that is the data that really caught our attention. This was published in 2022. What this graph on the left is showing is that when you look at female age from around the mid-thirties, if they have had ICSI, the chance of a live birth given clinical pregnancy significantly declines so around the mid-thirties, whereas age related decline is mitigated with PICSI. We then look at the inverse of this and consider the predicted miscarriage rate given a clinical pregnancy. This is basically telling us that for a 38 year old with a clinical pregnancy, if they had ICSI there’s a 45% chance they will miscarry. Whereas with PICSI that is reduced to around 15%. So that is a big difference.

They did also see a similar effect when they looked at male age. You can see on the left that the predictive live birth rate given a clinical pregnancy declines with male age from around the mid-thirties with ICSI. Whereas that is mitigated with PICSI. It’s clear that the effect in men isn’t as strong as the effect in women. Because if you look at the inverse of this graph, so we looked at the miscarriage rate given a clinical pregnancy for 38 year old male, whose partner is clinically pregnant, she will have a 25% chance of miscarriage with ICSI, whereas with PICSI that’s 10%.

The fact that the data shows that the strongest effect is in women makes sense because we know that eggs have the capacity to repair the sperm DNA damage, and this capacity reduces with age. If you are performing standard ICSI on an older patient, you’ve got a higher chance of selecting sperm with high sperm DNA damage, if you inject that into an older egg, you are essentially stressing out and already stressed egg. Now, obviously this is predicted data or predicted graphs based on real data, but they did return to the full trial cohort to confirm the effects of both age and treatment type on the odds of the establishing a clinical pregnancy and the subsequent odds of miscarriage.

What you can see on the last circle here is that in terms of odds of establishing a clinical pregnancy, only female age was a significant factor. This shows us that for someone who’s 35 or older, they have a lower chance of establishing a clinical pregnancy, which is what you would expect. In terms of the odds of miscarriage, it was both female age and treatment type. The red circle in the middle tells us that someone under 35 has a lower chance of miscarriage, as you would expect, and then on the one on the right, that is saying, for somebody who is 35 or older, if they have had PICSI, they will have a lower chance of miscarriage. Then for somebody who has had ICSI, this basically confirms that older women are the sort of ideal patients to benefit from this treatment type.

So that is what we use to determine our eligibility criteria. So we have decided that we are going to offer it to patients who are already having ICSI where the egg provider is 35 or older, and they’ve also got sperm suitable for PICSI. For PICSI you do need to have motile sperm. For sample such as TESE samples, which likely won’t have any progressively motile sperm, we won’t be offering it to these patients. We did think about only offering it to patients who are 35 and older, with a low ovarian reserve, that was suggested by other clinics and also just from feedback from the HAB Select trial because the PICSI procedure, especially at the beginning when you’re getting used to the technique, it does take longer, so it’s managing that workload in the lab.

I think knowing how much of a difference this would make, we can’t justify offering it only to a subset of those patients at this stage. There are other cases that could benefit from PICSI. For example, recurrent miscarriage and where the sperm provider has a high level of sperm DNA fragmentation. We’ve decided that we are going to look at this on a case by case basis with our clinical team.

The purpose of that is because really the doctors will just want to offer this to everyone and obviously we won’t be able to manage that amount of workload in the lab. It is likely that patients within those two categories will likely fall into the first category anyway. The next thing that we considered was the patient pathway and how we are going to effectively communicate with patients and allow them to make an informed decision. So for our main eligibility criteria patients, they will be seen in clinic, that could be the first clinic appointment, or it could be a follow up appointment following an unsuccessful cycle. They will be offered PICSI in clinic.

This is going to be, in our clinic, it’s going to be very much patient led and also scientific led. If they’re interested, they’ll be given the patient information leaflet which they can go away with and on that it’ll go through everything about PICSI and if they are interested, they will email the embryology team and then we’ll give them like a mini consultation. The purpose of that is really just to check that they have read the leaflet, they understand the treatment type that they’re having, you know it’s not just that somebody says to them you need to try this, you need to try this.

They need to really make sure it is an informed decision, and then if they still want to go ahead, then they’ll just return the consent form to us so that we know treatment can proceed. In terms of women who are under 35, but they are presenting with recurrent miscarriage, or high sperm DNA fragmentation, or it could be something else that the doctor thinks needs to be reviewed, or it could be that the patient just wants to try PICSI. These cases will be referred to our weekly scientific review meeting for discussion. The purpose of this is just to review the patient’s case.

It could be that they may benefit from another treatment option. For example, PGT-A or AOA, and then the embryologist will have consultation with the patient, just to go through whether that is the best treatment option for them and just to make sure that we aren’t unnecessarily doing PICSI for them. Then again, if they are proceeding we’ll get the consent form back.

In terms of our consent form, it’s just a general one. It’ll go through the lay description and who it will benefit, how it will benefit them, the risks, and what to do next. We also, on our consent forms, include a statement about the regulatory position on PICSI, because with add-on treatments they are subject to the HFEA traffic light system, which I’m aware may change, but at the moment what we don’t want is for the patients to go to the HFEA website, see this big red circle, and wonder why on earth are we offering them a treatment option where there’s no evidence.

Now this red status for PICSI, it’s old, that’s not in light of the more recent data. So it probably does need to be changed. But we just need to make sure that we are being transparent with our patients. In terms of the consent, that just goes to the acceptance of risks, aware of the cost, aware of the traffic light status, and it will also include a statement just to say that they are aware that we may need to convert to standard ICSI if we don’t see any bound sperm, because if they haven’t read the patient information, they may not know that.

When you are implementing any change, obviously you want to get your team on board. You don’t just want to make the change and all your staff wondering what on earth is going on. At The Hewitt, we do have multiple platforms that have allowed us to do that. For example, we have a journal club once a month. That is open to all staff disciplines and we just provide the summary of the evidence and our plans for implementation. We also have a clinical meeting which is typically attended by the doctors, senior nurses, and senior embryologists, but that is open to all staff across our two sites.

We also had CooperSurgical attend for a workshop, that was mainly for lab staff training purposes. But we did also have a talk by them for everyone to attend. Fortunately, it’s fallen quite nicely in line with our annual staff training day. At this day, every member of staff across both units attended and the importance of presenting it on these platforms so that all staff could learn and about the technique. We have had a lot of patients calling up about it. Also, so that they could offer any suggestions, express any concerns, and that type of thing really, just to get a team on board.

Being an NHS trust, we did need to get board approval. We did need to present a business case to our divisional board, which went through the rationale for offering PICSI, the benefits, we did a cost analysis because the trust obviously wants to check they’re not going to make a loss. It went through the risks of PICSI, the timescale for implementing it, and our plans post-implementation. I imagine if you are an NHS trust that wants to implement a new technique, you are going to have to get some sort of approval. And likewise, imagine if you’re a private clinic, you’ll have some sort of board that just wants to check they’re going to make money.

Then just finally a comment about validation and training. We’ll be using the PICSI Dish, the solid-state platform, because that is the one that is used for all of the studies. There is SpermSlow™, I think there’s been one study comparing the two, but most of the more reliable data is surrounding the PICSI Dish. When you introduce any new consumable into the lab, you just want to make sure that it conforms with HFEA regulation, is it CE marked, which is it isn’t UK CA marked at the moment, but I know CooperSurgical are working towards that.

The first thing that we did was a VOC test with a validated VOC meter just to check that on packet opening and, and during its time in the warmer that it’s not going to release any potentially toxic VOCs. If it did release any VOCs, our solution would be to off-gas the dish in advance. We’re currently in our temperature validation stage. What we are essentially doing is mimicking the pathway that the dish is going to follow throughout the PICSI process.

Seeing how long it takes to warm up in our warmers and how long it maintains an optimal temperature, and the same on our ICSI rigs, and the same on our heater stagers and our hoods. Based on how long it can maintain a temperature, that will help us determine the dish setup. So how many eggs can we inject per dish. In terms of training, we’ve got 15 ICSI practitioners across two sites, all will be expected to do PICSI. We obviously have ICSI practitioners that are more often in the labs who will prioritize those first. If anyone’s got any objections against PICSI, we do expect them to be able to do it.

A quick summary, if you are implementing a new technique, not just PICSI, it could be any, the first thing that you should do is look at the evidence to see if it supports its use and if so, use that to determine your eligibility criteria. Consider your patient pathway. How are you going to communicate with the patients and allow them to make an informed decision? Consider how you’re going to get your team on board. Consider if you need to get trust or board approval. Then also look at your validation and training plan just to make sure it is robust and make sure that you are not going to compromise patient treatment. Thank you very much.