Managing personal risk in IVF

How far is too far on new IVF techniques?

On last week’s post someone from the Better IVF Facebook group asked an important question which I decided I needed to ponder on more before I answered. She asked “Are you at all concerned by the lack of research and regulation around MST in the places where it is being practiced?.” MST is a great example of what I think the general consensus would be is a very fringe IVF treatment at the moment, mainly due to its lack of approval and access within primary treatment countries such as the US.

But the question Milly asks is very valid. How do we, as individuals, decide ultimately whether we will accept a lower standard of evidence applied to our own care in order to pursue gains that may not otherwise be possible?

Here’s an important first thing to point out. We are not public or IVF policy specialists. We do not have to require something to reach the highest levels of evidence before considering the treatment, because our window of opportunity for the treatment is usually limited to a far lesser timeframe than would be required to achieve that.

Secondly, we do not need to have something show efficacy at statistically significant levels or at all age cohorts, we can dive in and determine whether our specific age cohort benefited and whether, even if not statistically significant, it was positively trended.

So how far should we go? What standard of evidence should we decide is good enough for us? While I can’t answer for each one of you (and I encourage you to interrogate the studies that I personally chose to represent my own reasoning to doctors in adding certain items to my protocol with the stated goal of improving euploidy), I can at least share my own thoughts on this.

I’ll say upfront that I’m a business owner. I am comfortable making big decisions without always having a lot of data, and I am comfortable taking risks. My risk profile, in general, is probably higher than the average person. Your risk profile may be different to mine and this is ok. In some ways, I have taken the risk and spent money on this so that you at least take some degree of comfort from my case study.

But the standard of evidence that I looked for considered the following:

1. How big was the potential pay off? How many people benefited even if it was a small retrospective or prospective study?
2. What was the study set up? Was it randomised controlled, blinded or double blinded, prospective of retrospective
3. Were the results statistically significant for my age bracket? If not, were they positively trended? If not, how bad was the decrease (was it equal to the increase or was the potential decrease quite small)?
4. How similar were my cycle characteristics and demographics to that of the study’s participants. I would always prioritise the exact methods or dosages of studies where it had focussed in on a participant who was MOST like me.
5. Was there meta analysis that might further support its use. If one meta analysis was done and it wasn’t statistically significant, was it still positively trended?
6. Did the research track results through to not just live birth but beyond? Eg to age 2 or 3 or 5 years old?

If the ideal scenario didn’t exist: eg someone in my age cohort and cycle characteristics in a prospective, randomised controlled trial with over a thousand participants, I decided, personally, to accept less than that ideal standard of evidence.

My personal reasoning was this:

• I had limited time, resources and money. I had more money that others, but not unlimited.
• Getting to raise next and final child is more important to me than the potential downsides.
• I interpreted the risk as low because most of the studies had tracked through to healthy live birth so it appeared to me that the worst thing that could happen would be that my results would get worse. And based on my results at the time, I didn’t think my results could get all that much worse, so it was worth trying
• I didn’t want the mental load of forever wondering “what if I had just tried x or y, maybe my life would have been different.”
• I determined that even on the off chance that this may have some unknown detrimental outcome to me, I could not live my life worrying about possibility of unproven adverse effects.
• People in a worse position than me had been studied and it had improved results for them, there for it was reasonable to consider the things that improved cycle outcomes for DOR or poor responders, could work for an older woman. It wasn’t like was the first female in the world doing these add ons. Tens of thousands had done them before me.
• Even if I was the first…human trials are usually attempted after extensive animal IVF trials and then small trials on human research embryos, and hey, someone has to be first don’t they!
• I had also looked all the way down to anecdotal evidence and people’s personal experiences in Facebook groups to understand the potential side effects that aren’t usually called out in studies, and felt the potential downsides (primarily with HGH) were unlikely based on my presentation.
• Doctors and embryologists weren't going to help me with my euploidy problem. They believed that my age was the main factor for my results and it couldn’t be changed. So I knew if not them, then no one could decide this or help me. And fair enough they had their own risk profiles to adhere to, so it meant I would need to bring things to them and advocate for myself.
• I already knew that with protocols like The Bondi Protocol that specifically selected items could work more effectively together than as the sum of their parts. And it was partly this thinking that guided me.

What was the risk?

The biggest risks are:

1. That there was a worse outcome than in previous cycles, it it wasn’t just random cycle variation or as a result of doing IVF many months/years later than the previous cycle, it was directly related to the addition of the add on
2. That there could be some long term health impact to the mother as a result of the add on (where it is a medication)
3. That there could be some long term health impact to a resulting child directly connected to the add on

To the first risk, unfortunately most of the studies don’t do self control comparisons (where there are two groups that have one and a second cycle and the control group does the same protocol for the 2nd cycle and the test group makes the change) and even when they do they don’t report on what percentage of people had a WORSE outcome in comparison to the first cycle. So this is mostly something that we only have anecdotal evidence of. As a result, this needs to be a leap that we choose to take, or not.

I think it’s also fair to add though, that this is where listening to anecdotal stories can be helpful. Especially for cases where it is very clear, because people for instance, add HGH and then get empty follicles. Stop it for a subsequent, and then normalise follicles again. Add it back in a later cycle and it happens again. This still doesn’t say anything about whether that aberration will happen to YOU though. But it might suggest that you add all the other add ons EXCEPT HGH to start to manage that risk.

As for the second risk, there are a couple of cases for this protocol specifically where it may be worth doing bloods: for Met and for HGH. While I did not, if you have reason to believe you may have high IG4 levels or very low insulin levels, then it would be safest to do this.

And for the third, we have to be honest and say that many of the things in these studies simply don’t have the longitudinal data to tell us this information. However, if we can say that as a result of these add on treatments, an embryo is made euploid, that goes a long way to forming a hypothesis that a euploid embryo created with these add ons would have the same types of outcome as any other euploid embryo that has been researched.

So let’s go through the standard of evidence for each of the things that I talk about in the “Bourke Euploidy Protocol”.

1. HGH: Mostly retrospective trials, one prospective, but some good examples. Has one great study very specific to normal responders and non DOR women. Meta analysis has not been done on these women, only on poor responders.
2. Metformin: A combination of studies and two really good retrospective studies specifically on women WITHOUT pcos or high insulin levels. No meta analyses.
3. Calcium Ionophore: A range of studies (some retrospective and some prospective) that show statistically significant impacts in most age ranges, and positively trended in others. Plus two meta analyses, one that suggests euploidy / quality changes have low evidence (but those studies still positively trended), and another that suggests enough evidence on euploidy. Unfortunately most studies are on embryos from people who have fertilisation problems rather than normal cohorts which is a downside.
4. PICSI: Individual studies that suggest it certainly doesn’t have a detrimental impact, and an excellent, large, prospective randomised controlled trial that shows very significant benefits to live birth.

Now let’s turn to something much more fringe than all of these like Maternal Spindle Transfer.

I don’t necessarily think everyone should do it. But the reason why I said last week that it needs to be considered after you’ve exhausted the other euploidy add on options and they haven’t worked is this:

In terms of evidence, the things that I think make MST still a good choice for people who don’t want to go down the full donor route are as follows:

• The original technique is more than 20 years old. It resulted in the birth of over 30 children worldwide before being banned by the FDA.

https://www.fertstert.org/article/S0015-0282(23)00291-1/

The reasoning was on mostly ethical grounds in that it may constitute germ-line gene therapy by introducing both donor mitochondrial DNA (mtDNA) and possibly the patient’s own mtDNA to the gene pool. Germline gene editing is banned in the United States by acts of Congress although there is no federal legislation that dictates protocols or restrictions regarding human genetic engineering. So in essence the reason for is banning was not about safety nor efficacy, it was about the fact that it fell under the potential legal definition of germline gene editing.

• In the UK AND Australia however, this technique has been approved for use. https://www.hfea.gov.uk/treatments/embryo-testing-and-treatments-for-disease/mitochondrial-donation-treatment/ (legislated in 2015)

https://www.health.gov.au/our-work/mitochondrial-donation#:~:text=Used with in-vitro fertilisation,woman (the mitochondrial donor) (legislated in 2022)

Although its use is currently limited to people with SEVERE mitochondrial diseases to avoid passing that on to their children, rather than ageing oocytes.

Nevertheless, these two countries however would be considered two of the most stringent in the world as it relates to safety and efficacy of any technique. So looking to them as it relates to its safety is a sound approach.

• Greece is the only country in the world that specifically allows MST for use related to ageing oocytes. And they legislated this only in 2018 so it’s only been occurring for the last 6 years, and if we remove covid from that timeline, really only for the last 4 years.
• Albania is an eastern European country that has been coming up as one of the best performers with MST. They don’t have legislation related to it so its a bit of a legal grey area there. The vast majority of folks who are doing MST are going there f or it because they are experienced. The specific clinic name is: IFG/SAGA Clinic and the group to go and discuss this on further is here: https://www.facebook.com/groups/974027114272766/

It is important to note that overall, Albania is ranked lower in terms of its overall medical standards, so this is something to consider, but the anecdotal experience of women who have attended say the care and standards of this specific clinic is exceptional.

https://sagaclinic.com/portfolio/mitochondrial-transfer-mitochondrial-donation/

And this is likely because this IVF clinic is part of a group that spans Turkey, Ukraine, Slovakia, Albania, and Australia.

There are also considerations around the donor cytoplasms used themselves, such as your resulting child’s access to that donor given their bodies will contain that person’s mitochondrial DNA. Albania has a less established legal framework for oocyte donation, while Greece has a highly regulated donation system (although it is strictly anonymous). It’s probably easier to find an oocyte donor you may know to give you their cytoplasm though than their DNA so that’s something to consider. You could arrange a known donor such as a sister or friend.

• As of 2023, the very first pilot prospective study was released from Institute of Life-IASO IVF Center in Greece. Twenty-five infertile couples with multiple previous unsuccessful IVF cycles (range, 3–11), no previous pregnancy, and no history of mitochondrial DNA (mtDNA) disease participated. The study focused on women <40 years, with previous IVF attempts characterized by a pattern of low fertilization rates and/or impaired embryo development

https://www.fertstert.org/article/S0015-0282(23)00136-X/fulltext

Twenty-eight MST cycles produced 6 children. This makes sense given the context that this focussed on women who already had trouble getting to blast. If you DON’T have trouble with follicles and getting at least a couple embryos to blast, but all the embryos you produce are aneuploid, then this technique is really the best next step and most likely to produce an outcome without having to turn to 100% donor oocytes.

So with all that said, you can see there isn’t a hard and fast rule here for deciding whether or not a new technique is one you should avail yourself of. You might decide that the above information is not enough for you to take the risk, or you might decide its plenty. I think it partly comes down to how much of a dead-end you’re at with all other avenues, your finances, your own risk profile, and how strong your desire for a biological child is, and whether that overrides any concerns you may have. And for MST specifically, how able you are to travel out of country.

I’m curious as to how you all consider these risks yourselves and if this helps you assess the risk more deeply in your own case.