Any advice, about to embark on 3rd IVF

[GingerBrummie]

Hi all,
Some advice pls… Ive been TTC for 3 years & classed as unexplained infertility. Im 38 (39 next month) & DH is 48.
When TTC naturally I tried everything, acupuncture, Chinese herbs etc etc. I take a pre-natal, Ubiquinol, Omega 3 & extra Vit D, non-smokers. Im “fortunate” enough to get 3 free NHS IVF cycles but sadly the first 2 failed. First time I used gonal F got 19 eggs, 11 fertilised but by Day 3 I only had 2 average embroys to put back & none made blasts. Second cycle I changed to menopur, got 11 eggs & 8 fertilised, again 2 average embroys on Day 3 but no blasts on day 5. I had both put back. I always start spotting at either 7 or 8dp3dt. Which is equivalent of 11dpo, docs think this is fine, plenty of time for embryo to implant & apparently “spotting” is ok. I was even on 3 progesterone pessaries per day but it never stopped my period!
Anyhow Im now at crossroads, part of me thinks I just have rubbish egg quality hence no good embroys (lots of fragmentation on first cycle) but other part of me thinks maybe I should pay for some private tests before my last cycle. I had an appointment with Jan Brosens of the Coventry Hospital about NK killer cells & he is happy to carry out a biopsy as in all the 3 years Ive tried Ive never seen a bfp which I think is strange so perhaps my body is killing embroys? All my tests & DHs are fine (hycosy, progesterone, bloods etc etc). However Im also thinking is this a waste of time & money, as I cannot try naturally whilst he does the biopsies.
So my Qs are….

• Anything else I can do to help egg quality before my last NHS round?
• Shall I bother with NK killer cells test
• Should I arrange a sperm DNA fragmentation test even though we always have high fertilisation rates & samples always been good

Any comments welcome & sorry for long post

Hello, sorry to hear about the unsuccessful cycles.

Issues with IVF not working can either be down to the embryo or the endometrium. In most cases the issue is with the embryo. I was I guess lucky in a way, I have never had BFP either and my embryos looked great, so it's quite clear that the issue for me is with the endometrium. But others may well have issues with the endometrium alongside issues with the embryo, and targeting just the embryo may not solve the problem.

Firstly in relation to the embryo:
From your story it sounds like you are getting good amounts of eggs, good rates of fertilization and then quite a high drop off before day 3, which could well be due to egg quality. There are a few people on here who have done well with natural modified IVF, which you might want to explore. Have you had any tests to look into endometriosis, like a laparoscopy as this can cause issues with egg quality. It sounds like you're doing the main things they advise for egg quality. The book it starts with an egg is often recommended on this subject.

You've also mentioned sperm tests as a potential avenue to explore. Is your DH living a healthy life or are there things he could improve on? My understanding is that if there are issues with fragmentation then a lot comes down to a healthy lifestyle: healthy diet, low alcohol intake, not smoking, avoiding heat around the genitals and taking vitamin C. If DNA fragmentation picked up an issue then what would be the solution, this might be a good way to assess whether this will help. Also, remember it take about 3 months to notice any improvement when it comes to lifestyle changes with sperm.

Now the endometrium:
Issues here could be to due to issues with receptivity: there is a test called the ERA but this is only really helpful for determining if the transfer of a frozen embryo needs to happen at a different time than the standard protocol. I note you've just had fresh cycles so far.

The microflora also needs to be right, there is a test called the EMMA ALICE, usually done at the same time as an ERA. In my case I was found to have 0.00% good bacteria which had to be treated. Can you explore this?

Structural issues affecting implantation can also be an issue, I note that you've had a normal HSG so it's unlikely you need to look into this further.

Then there's the immune stuff, the evidence base is pretty patchy in relation to this. I'm on the waiting list to see Prof Brosens, my understanding is that if you are found to have very high NK cells then you can try steroids and intralipids. There is no evidence for this stuff at the moment, but I think we often reach a time where we've tried the evidence based stuff.

In conclusion my advice would me

• Have a read of it starts with an egg to make sure you're doing all the recommended stuff.
• Make sure your partner is doing all the advise stuff too
• Ask your specialist if investigations for endometriosis should be explored.
• Ask about/ do some research on natural modified IVF.
• Consider the ERA EMMA ALICE.
• By all means do the NK stuff, I'm planning on doing it as I've done everything else, but I would also consider all these other things.

Also on the point about spotting you could ask for progesterone injections as well because pessaries aren't always enough for everyone. There are two types, either subcutaneous or intramuscular. I bled before OTD on pessaries only but not when I added injections

Hi @IndigoNC thanks for tip re injectable progesterone, perhaps I will also insist they take a blood test to make sure its not dropping too quickly, although their OTD is equivalent of 17dpo which in my opinion is quite late so probably normal that I would start bleeding at the equivalent of 13dpo with spotting before.

@Gardenlady543 thanks so much for the detailed feedback, its really helpful.
Ive bought & digested the book already! I stuck to the ‘standard’ vitamins but steered away from DHEA & melatonin which looked a bit controversial. My husbands diet etc is pretty perfect, doesnt smoke, barely drinks, eats lots of nuts & has taken the wellman conception vitamins for the past year!
My lining has always been good, both cycles was 13/14 mm triple layer.
Re endo… NHS wont do a laparoscopy as I have no symptoms, no painful or heavy periods etc. I would need to go privately, I will do some research on clinics, would be good to rule it out.
Re the NK Killer cells test, I asked the professor what he thought about the Chicago tests as I noticed lots of clinics do this, his view is that its massively outdated & a waste of money. Im still not convinced thats my issue & not trying for 2 months is so hard.
Regarding the microflora, I went to a private clinic recently as I always spot before my period, from 11dpo onwards, NHS wasnt bothered, they said spotting doesn't prevent a pregnancy but I wasn't convinced. Anyhow private doctor did lots of tests, inc progesterone & everything came back normal, she couldn't find a reason for the spotting. She also checked my bacteria & checked for mycoplasma which was non existent, so I think thats fine.
I will ask my NHS if they offer mild IVF as I need to focus on less eggs but better quality.
Thanks again for the response. Where are you currently on your journey?

Hi @GingerBrummie

Sounds like you and your DH are doing all the recommended lifestyle stuff then.

That's a really good lining thickness. I think people are prone to bleed prior to the OTD in fresh cycles. I bled from 8dp5dt and I was told it was normal as it was the equivalent of 13dpo. In FETs I've never bled as the medication holds it off. I think having your progesterone level checked would be a good idea, it sounds like you have a good amount of follicles though and your body would be contributing a good amount to the total progesterone so I wouldn't be surprised if it comes back fine. If you implanted your body would produce HCG which will stimulate the corpus luteums to make more progesterone and hold off a bleed.

I think exploring the endo investigations would be a good idea. Silent endo can have a significant effect on egg quality.

How did they check the microflora? They would need to have taken an endometrial biopsy and assessed it with an EMMA.

The Coventry clinic seem to be the best place to do the NK stuff, it's clearly the cheapest place and seems to take a research based approach. That's why I thought it was worth trying. My understanding is they like to take biopsies in 2 separate cycles and tell you not to ttc in those cycles, so I can see it would delay things a bit.

My journey is complicated! Started TTC in October 2019, after a year of no BFP. We had investigations, my hormones were normal, DH sperm looked good. US I was told was normal but actually I had a thin lining.

We got a great result from the fresh cycle, 9 blasts, I developed progesterone hypersensitivity, transferred a blast still, but the cycle was unsuccessful. Had the first FET after that again a BFN. I said this makes no sense, how have I never had a BFP with such high rates of high quality embryos. We PGT-A tested the remaining embryos, 1 doesn't survive the thaw, 1 is aneuploid the other 5 are euploid (a 83% rate of euploid embryos- which is amazing as I'm 35 not 20!). I say "this makes even less sense now" and we go into a huge amount of tests:

• thrombophilia genes- 1 abnormal gene found, doesn't explain anything really.
• autoantibodies- normal
• ERA/EMMA/ALICE- I went through a mock medicated FET and on the day they would transfer a biopsy was done, it took my specialist 3 attempts to get it, the lining wasn't actually there, she mentions Ashermans. While waiting for the biopsy results I see a specialist in it, I have a HSG- completely normal. Biopsy results come back saying I have no good bacteria in my uterus (>90% is needed for good outcomes) which I have treated and I'm pre-receptive.

We think we've cracked it. I go into the 2nd FET this time we're using a confirmed euploid embryo, I'm on aspirin and heparin, the microflora has been treated and I have the transfer timed as per the ERA result. Another BFN. The chance of success should have been 70%.

I'm told my lining has been thin towards the bottom of the uterus in the 2 FETS and when I had the biopsy. My specialist mentioned a hysteroscopy. I'm due to have it in 1.5 weeks time. Then I'll probably repeat the EMMA and ERA. And await the Coventry clinic appointment date. I'm probably looking at my next transfer around November, doesn't everything take forever!

Hi @Gardenlady543 I cant lie…. reading your situation gave me a slight headache! It sounds confusing, intense & unfair, how do you cope with it? Im struggling with the whole infertility thing now, too many of my friends are now having second babies, sadly Ive had to lose touch with them, Im just not emotionally strong enough to be around newborns & pregnant women.
Anyhow…. thanks for sharing. Regarding the bacteria, the doctor took a vaginal swab & had it tested for mycoplasma & ureplas which can cause infertility plus some other ‘stuff’, it all came back negative. I assumed microflora would be included, my mistake. Does this still matter if its an IVF cycle as I would have thought it may not matter?
You are right re the Coventry clinic, its 2 cycles, I need to call them when I next ovulate, the cycles do not need to be back to back.
If you dont mind me asking, are you NHS or private? My NHS offer next to no tests so Im assuming you’re private.
It sounds like its only a matter of time before you get to the problem & knowing you can produce & freeze good blasts must be reassuring.
Sadly at 38/9 they start talking about donor eggs, but Im not there yet, I still want many more cycles before I consider that.

I just wanted to say that it's perfectly normal for it to take 3-4 cycles to get to an evens on chance of a BFP if you have a 20% chance each time, so a few cycles more than that to achieve a pregnancy is not unusual.

I didn't ever believe this and thought there was something wrong with me but it turned out I needed to do three cycles and four transfers (7 embryos in total) to find our lucky egg. We had our DD last year and are just about to start our second cycle for a sibling.

I'm not trying to be dismissive whatsoever, but I just wanted to share my experience.

Egg quality looks like it could be a bit of a challenge for you, maybe ask about DHEA or testosterone as I believe this is prescribed empirically for older ladies (more generally in their forties) and can help with egg quality.

My consultant advised against a sperm fragmentation test as he said any issues would have been picked up as part of the clinic's SA and because we also had good fertilisation. He also totally rubbished the NK test but I pushed for it but wasn't treated for anything. Could probably have saved a few hundred pounds there 🤷🏻‍♀️

Ask them to prescribe you steroid, blood thinners and aspirin empirically. It won't do any harm and it worked on our successful cycle. You could also try lubion progesterone injections if you have any doubts about your levels. My doctor said the pessaries are absolutely fine want to try them for our next round. They cost a fair bit more but there's only one jab instead of shoving vag tabs in all bloody day, which I absolutely hate!

Really hope your next transfer is the lucky one. It's such a hard journey but statistically at your (and my age!) after three cycles you have roughly a 55% chance of being successful so the odds are in your favour 🤞🏻

@GingerBrummie lol at my explanation giving you a headache, I did say it was complicated 😂

I am private, me and DH wouldn't actually qualify for NHS treatment until October this year. Knowing all the issues we've found to date I'm glad we didn't wait, as it wouldn't have worked. We went with an access fertility package which has definitely helped with the costs. But we've had to pay for all the investigations, we've spent about £16k so far. It has been me pushing for all the tests. I'm a doctor, not a fertility doctor. But I have read a huge amount of the evidence.

I had no idea about how important the microflora was until I read a book on endometrial preparing in IVF. It cited a number of studies like this one https://doi.org/10.1016/j.ajog.2016.09.075 which separated women with more than 90% lactobacillus (good bacteria) in their uterus vs those with less than 90% lactobacillus, the outcomes were statistically significant:
Implantation 60.7% vs 23.1%
Pregnancy 70.6% vs 33.3%
Ongoing pregnancy 58.8% vs 13.3%
Live birth 58.8% vs 6.7%

Well with 0.00% I has no chance. It's likely that the mirena coil I had for 6 years took the dysbiotic bacteria up there and it flourished. Despite eating a very healthy diet with lots of probiotics, I had the worst possible microflora. I took 7 days of targeted antibiotics followed by 10 days of vaginal probiotics. And now I take the vaginal probiotics every couple of weeks and an oral one called femdophilus daily. There are vaginal swabs that look at the various forms of bacteria and they might give an indication of what's going on in the uterus, but the gold standard is the biopsy with the EMMA.

Having the good embryos is definitely reassuring, but at the same time all the embryos in the world won't help if they never implant. Once I've had the hysteroscopy and the repeat EMMA and ERA and the NK stuff, that's all the tests possible. After that all I can do is keep having transfers.

Gosh I feel you with the issues coping. I cannot deal with anything about pregnancy or birth. I don't go on social media, I avoid the news, I cut people out if they get pregnant. Maybe I'll get better at dealing with things in the future, but right now it's too hard. This is about self preservation. I am on these forums a lot as this is now my main forum of socialization. It helps to have other people to speak to going through the same things.

Hi @FingersXssd83 thanks for your positive story. Im really glad you got there in the end, I can only dream what that must have felt like and best of luck for the new round.
It does help to be reminded it can take a few cycles, as its very easy to go down a rabbit hole of thinking something is wrong & suddenly Im so much poorer as a result! Each test costs so much. Thanks for the advice re aspirin & steroids, were these prescribed privately or NHS? My docs at NHS dont believe in anything extra, they are very standard, one size fits all. Sometimes I wish I hadn't bothered with NHS & went straight to private, I feel like private run more tests & monitor you more closely which may be okay if I were still young! When TTC naturally I did try aspirin a couple of cycles as I heard it helps but I dont like to self prescribe stuff.

@Gardenlady543
Sounds like we are similar in our coping mechanisms, Im glad I now get to WFH as I no longer am pestered by people in the office asking when I will have kids! Even seeing pregnant women on the train was difficult. I came off FB a long time ago. I have next to no friends but Im sane & I know its only temporary.
Regarding the bacteria, I have taken a couple of courses of antibiotics post egg collection but Im guessing its something more specific, I will look into the EMMA & thanks for the link.
Ive decided to do my last round of IVF with NHS before I see Prof Brosens as Im starting to think its an egg quality issue for me. I see do many women getting easily to Day 5, but I can barely make it to Day 3 with my embryos. Im trying to eat more protein, although I always have & will ask about DHEA.
Happy Friday

@GingerBrummie it's important to take the right antibiotics to target the dysbiotic bacteria present. So based on my analysis I took 7 days of co-amoxiclav but my friend needed to take metronidazole. It's also important to replenish the good bacteria with vaginal probiotics for 10 days after, I use canesflor.

For DHEA, my friend with a DOR takes this. She arranges blood tests through medichecks for her DHEA and testosterone level as my understanding is you need to keep the level in range.

Thanks @Gardenlady543 I just called a private clinic for the EMMA test which also includes the Alice test & they charge £1,200! Im in London so maybe its more pricey here.
If I add up what Ive spent over the past 3 years on acupuncture, private tests, expensive vitamins like Ubiquinol, clomid monitoring for 5 months I would feel sick, its easily in the thousands, probably a deposit for a house! Sorry for the whinge, times like this I wish money was no problem.

@GingerBrummie that's a pretty standard price, the ERA costs £1000 at my clinic and it costs £500 to add the EMMA and ALICE on, so a total cost of £1,500 plus you need to pay for a course of FET medications which usually costs around £200-300.

@GingerBrummie I was an NHS patient at a private clinic as we transferred out funding across. That's so tough that the NHS won't allow you to try them.

I think it's worth considering though that if those were 100% going to help then I am sure they would prescribe as they are also in the game of getting you pregnant as quickly as possible.

Try to hang in there and let us know how you get on x

Thanks @FingersXssd83 :)