During that last round of IVF I felt like I was fighting an uphill battle. Diminished Ovarian Reserve, Poor Responder, High FSH levels. All of the odds were against me, and I knew it. That didn’t stop me from hoping, though. From reading all the research and taking all the supplements, using all sorts of relaxation techniques, standing outside on a full moon downing royal jelly (okay, not that last one!). You get the idea. I was doing everything I could.
We tried a new protocol, I’d be on DHEA + we added in human growth hormone to my protocol. Woop! We were in! My follicles grew, and by the time egg collection came we retrieved 12 eggs!! TWELVE! I was considered a normal responder!! We were over the moon, and I was quietly patting myself on the back for a job well done.
The thing with celebrating early is that you leave yourself open to all the other hurdles. Like fertilisation.
Of our 12 eggs, only 5 eggs fertilised. All my eggs were mature. The sperm sample was good. And less than half, only 41% fertilised. Sucker punch to the belly - I felt like all my hard work was for naught. My disappointment shouldn't be mistaken for ungracious - I am grateful we that had five little embryos, and that five is better than none. I’m grateful for that.
However, I’m a determined person and want to increase my odds however I can. I’m looking for something more than 41%. The biggest thing for me was should I have asked for ICSI, rather than IVF?
It took me a while to understand the subtleties between the two:
Fertilisation by IVF
With IVF the eggs are placed in a fancy liquid into a glass petri dish and the washed sperm sample is added to the dish near the egg. The sperm hopefully find their way to the egg, burrow in past the shell and cause a chemical reaction (which stops other sperm from joining the party). The sperm kicks off a round of meiosis to bring the chromosomes together and causes fertilisation.
Fun side note, IVF stands for In Vitro Fertilisation - turns out In Vitro means “in glass”.
Fertilisation by ICSI
An embryologist will select a single sperm from the washed sample. This sperm will be put into a needle which is then carefully advanced through the outer shell of the egg and the egg membrane. The sperm is injected into the inner part (cytoplasm) of the egg, allowing fertilisation to take place.
Most clinics will only use ICSI if there is an issue with male factor infertility (such as low sperm concentrations, motility or poor sperm morphology), where the benefits are clear. They might also, at a stretch use ICSI for couples who have had pervious IVF rounds with low or no fertilisation with mature eggs that should have fertilised.
There are some risks with ICSI. In IVF natural selection takes care of things - the fastest and fittest sperm wins the race. However, with ICSI it’s not nature that makes the selection, but an embryologist. If the sperm has a chromosomal abnormality or a genetic defect, this might be passed on to the embryo. In some cases, the chromosomal abnormality may result in a miscarriage. However, this is also possible when fertilisation is done by IVF. Chromosomal abnormalities aren't specific to ICSI.
One concern is that ICSI requires the removal of cell-to-cell communication structures. When oocytes are processed for ICSI an embryologist will remove the outer cumulus cells around an egg. These cells have little extensions which penetrate through the shell of the egg and touch the egg itself, forming a little communication network between the surrounding cumulus cells and the egg within.
With ICSI the cumulus cells are dissolved with an enzyme, and helped away with a little shearing of the pipette. This helps the embryologist see inside the egg to check that it’s mature (which is to say that it’s thrown out the excess maternal DNA in the polar body). It also ensures that ICSI is done in a relatively empty area of the egg, rather than through any maternal chromosomes.
While the cumulus cells typically falls off naturally over after fertilisation, with ICSI the communication between the egg and cumulus cells is removed well before fertilisation. It’s been shown that this effects the fertilisation rate and subsequent embryo quality negatively. (Source)
There have also been some animal studies in mice that show that with ICSI some genes can be imprinted incorrectly, suggesting that removing the communication network between the cells and the eggs could interrupt a gene printing process. (Source)
Another risk is the introduction of PVP into the egg and the effect it has to both the egg and the sperm. In some ICSI cycles an embryologist will use PVP (polyvinylpyrrolidone, which is a thick syrupy polymer) to slow down the sperm so they can be easily managed with the pipette. Without PVP sperm are fast and would be impossible to catch and manage for fertilisation.
One study (Source) reported that exposure to PVP prior to ICSI damages the sperm plasma membrane, allowing thiol-reducing agents to gain access to the sperm nucleus (not a good thing). It’s also possible that PVP loosens the make up of the sperm nucleus, which will eventually condense into cells.
It’s suggested that fertilisation rates and clinical pregnancy rates could be improved by using a PVP- free solution with ICSI. (Source). That instead of using PVP, an embryologist should use a hyaluronate solution (hyaluronate is naturally found in the reproduction tract) instead. (Source)
Another risk is that the success doesn’t just ride on the quality of your eggs and sperm but on the skill of the individual performing the procedure and the overall quality of the laboratory. It’s a pretty hefty chance to take, so fingers crossed for an amazing embryologist. You might want to have a conversation about your clinic's embryologist experiences.
Alright, here are the questions I had:
- Is there a better fertilisation rate with ICSI over IVF?
- Exactly what happens with ICSI?
- Will ICSI effect the embryo quality?
- Is there a better transfer rate and pregnancy rate with ICSI over IVF?
- What is Rescue ICSI, and does it have a better fertilisation rate?
- What is IMSI? Does that have a better transfer rate than ICSI?
I did an awful lot of reading and googling, and here is what I found.
ICSI TECHNICAL PROCEDURE
- Immediately after egg collection, the oocytes (eggs) are evaluated to see how mature they are. Eggs that are clearly not mature are discarded.
- Cumulus cells are removed from the oocyte. First with a enzyme solution and then by moving through a pipette to shear the cells off.
- The oocytes are evaluated again to assess how mature they are and their integrity to ensure they’re suitable for ICSI.
- Sperm are washed with a viscous medium, and analysed. One sperm is selected.
- The selected sperm is immobilised by breaking it’s tail, and aspirated into the needle.
- The oocyte is held in place with suction to the holding pipette, and the injection pipette is pushed against the oocyte shell. Once at the centre a break occurs in the membrane, which pushes a flow up into the injection pipette.
- The sperm is injected into oocyte.
ICSI VS IVF - FERTALISATION, EGG QUALITY AND PREGNANCY RATES
I really struggled to find clear studies on this. I wanted something concrete, a proper study rather than a clinic’s promotional success rates - most spout something along the lines of 70-85% of eggs fertilise. The tricky thing with that amazing rate is it's a bit biased. ICSI is often used to treat male-factor infertility where fertilisation is the main hurdle. This means that the eggs used in ICSI cycles are typically high quality and collected from young fertile women - a very different skew from the typical IVF patient range.
I did find one study, done in the Netherlands in 2005. It's called Conventional in vitro fertilization versus intracytoplasmic sperm injection in patients with borderline semen: a randomized study using sibling oocytes. (Source). Definitely a mouth full but had some interesting results.
At first I discounted it as being 10 years old, but when I realised that it was one of the few studies I could find that was relevant and that rates could only have improved as the technology has, I took a look.
Here’s how it worked: each couple in study had a selection of their eggs split into two groups: Those to be fertilised by IVF, and those to be fertilised by ICSI. This get’s around the ICSI bias, as the eggs are likely to be the same quality across both methods.
Some couples eggs only fertilised with ICSI, and some with both ICSI and IVF, and the results are split along those lines:
Couples whose eggs only fertilised with ICSI and not IVF.
This group is likely to include those couples with male factor infertility.
Couples whose eggs fertilised both the ICSI AND with IVF.
Down to business, how’d they do?
Group IVF -
IVF Fertalisation Rates - Of the eggs in the IVF group, 0% fertilised.
ICSI Fertalisation Rates - Of the eggs in the ICSI group, 51% fertilised.
IVF Fertalisation Rates - Of the eggs in the IVF group, 51% fertilised.
ICSI Fertalisation Rates - Of the eggs in the ICSI group, 51% fertilised.
Pretty consistent results, right? ICSI fertilisation rate is consistent with IVF, if your eggs and sperm are able to be fertilised by IVF. If your eggs/sperm aren’t able, you may loose all your eggs to trying IVF.
I guess this up to you - if you think it's worth taking the chance, then IVF and ICSI have pretty similar fertilisation rates. If you’re in the borderline group, you can avoid unnecessary fertilization failure with ICSI.
In the study, embryos were put into four buckets (1 - 4) based on the number of cell divisions and the fragmentation. They were looking for the best: Type 1 embryos with equal sized cells with no fragmentation and Type Two, with equal sized cells and less than 20% fragmentation.
It’s important to remember this is only a visual guide, and an embryo that looks good may also be chromosonally abnormal, and thus not viable.
Group IVF -
Of the embryos that fertalised in the ICSI group, 77% were Type 1/2.
Of the embryos that fertalised in the IVF group, 72% were Type 1/2
Of the embryos that fertalised in the ICSI group, 83% were Type 1/2
I was surprised by this, but glad to see that ICSI didn’t harm embryo quality anymore than IVF does. In fact, ICSI embryos had consistently better visual quality than IVF.
These two are the proper indicators of success - how many resulted in a BFP at the first beta, 15 days post egg retrieval (which I’m calling pregnancy rate) and how many resulted in a positive pregnancy, with a heartbeat at week 12 (ongoing pregnancy rate).
Group IVF -
Of the embryos that fertilised in the ICSI group, the pregnancy rate was 54%.
Of the embryos that fertilised in the ICSI group, the ongoing pregnancy rate was 42%.
Of the embryos that fertilised in the IVF group, the pregnancy rate was 43%.
Of the embryos that fertilised in the IVF group, the ongoing pregnancy rate was 36%.
Of the embryos that fertilised in the ICSI group, the pregnancy rate was 53%.
Of the embryos that fertilised in the ICSI group, the ongoing pregnancy rate was 50%.
Here is the most convincing evidence for me - both ICSI groups has a higher pregnancy rate AND a higher ongoing pregnancy rate than IVF.
There is a third option, which is Rescue ICSI. If no eggs are fertilised via IVF, some clinics will take those eggs and use ICSI to fertilise them. This comes with risks, because if a sperm is already inside the egg the resulting embryo will have chromosomal abnormalities.
The research is also not clear. Some studies (like this one) suggest it might be worth a shot if none of the eggs that should have fertilised did. Other studies (like this one) suggest the odds aren't worth the cost as the success rate is so small.
ICSI VS IMSI
With ICSI an embryologist will do a sperm morphology analysis and sperm selection at a magnification of 400x. With IMSI, it’s thought that bigger is better, and this is done at an extremely high magnification (8000x). If you want to see what the difference looks like, here is a youtube video.
This is relevant particularly during sperm selection, as IMSI shows finer details and it is easier to see sperm that have head vacuoles or other abnormalities. One study (Source) found that between ICSI and IMSI the fertilisation rate was the same, but the pregnancy rate was higher and the miscarriage rate was lower for IMSI than ICSI.
It's a pretty personal choice.
- ICSI and IVI have the same fertilisation rate when you discount the male factor bias. However ICSI has the better pregnancy rate, but it depends on the clinic (and whether they use PVP in their ICSI process).
- There's the concern that by removing the cumulus cells in ICSI alters the gene imprinting process.
- If you are going to go the ICSI route, push for IMSI instead - as it has an even better pregnancy rate since the embryologists can see the sperm better during sperm selection.
Personally, I'm leaning towards either half and half or full ICSI/IMSI the next round. The benefits of ICSI I think well outweigh the risks of conventional IVF not fertilising... It's a tricky choice! It's hard to know what the right choice is. Hopefully my body will cooperate and the next round will be soon. I plan to discuss it with my RE, anyway.
QUESTIONS TO ASK YOUR RE
- Does the clinic offer ICSI, even if you don't have male factor infertility?
- What are your fertilisation and pregnancy rates like for half ICSI, half IVF fertilisation method?
- Do you use a PVP-free solution in your sperm selection process?
- Do you have the tools to offer IMSI?
- How experienced is the embryologist who will be performing ICSI on my eggs? How many ICSI procedures have they performed?
- Do you offer Rescue ICSI, and this is an option for me?
As always, I'm not a professional or a doctor - my experience is just that, my experience. I've done an awful lot of reading and research which I'm happy to share. If you do have concerns about IVF vs ICSI, talk to your doctor.