Dear Professor Winston,
My husband and I have just experienced our seventh failed IVF cycle using donors and we would be very grateful for your advice. It has been a very long process and I apologise in advance for the length of the following explanation. We appreciate any time you can spare to consider what we are finding to be a very challenging situation (to say the least). Our specialist, has said that I could try intralipids or IVIG (intravenous immunoglobulin) if we were to try again, but we know in the past he has not been very convinced of their efficacy. I can see that you have discussed immune therapy in past questions but I have the pain condition Complex Regional Pain Syndrome (CRPS) and we don’t know how much this is affecting our outcome and whether these treatments may actually be what I need, if they can make a difference. We have been trying to have a family since 2008. After failing to conceive I had tests done in 2010 when I was found to have an FSH level of 19. A subsequent AMH test showed a subfertile result. My husband and I were both 36. After my husband’s tests we were advised to try ICSI with a donor. My younger sister kindly helped us. On our first cycle (November 2010) we had two embryos transferred and I became pregnant but miscarried at six weeks. The CRPS normally only affects my limbs but after using injections as part of the buserelin treatment I experienced the extreme heat of CRPS pain in my groin area. I don’t know if this caused the loss of pregnancy. My pain specialist explained it is possible for CRPS to affect internal organs but not common and people with CRPS have had successful pregnancies. There is no available treatment for the condition that can be used in pregnancy. I was careful to use the buserelin nasal spray after the first cycle, as opposed to injections, but in every subsequent cycle I have had this sensation of a very high temperature around my uterus at varying times after embryo transfer. For every cycle I have had 1200mg Cyclogest as 400mg pesssaries (taken vaginally) and 8mg daily of estradiol. We undertook a further two cycles with my sister’s eggs. The second (April 2011) was a fresh cycle as we had no frozen embryos, with a faint positive result but I miscarried shortly after. We had one frozen embryo from that cycle and in our third cycle (2012) I became pregnant but miscarried at seven weeks. At this point we did finally get NHS funding for our fourth cycle but only if I used my own eggs-the result, predictably, was negative. I was referred to the Miscarriage Clinic but nothing significant showed up. I have been taking appropriate vitamin supplements since the beginning and was told to take additional high dose folic acid and aspirin and steriods during treatment. We returned to the IVF Centre to our specialist who suggested we use a clinic in Cyprus and after further semen analysis it was recommended we use both male as well as a female donor for our best chance. We went to Cyprus for our fifth cycle (November 2013) but the result was negative. We weren’t told of any problems with the embryos although none were suitable for freezing. Our sixth cycle (April 2014) we returned to Cyprus and had new donors. I became pregnant but it was a blighted ovum and I miscarried at nine weeks. Our most recent time (December 2014) we had new donors again and were assured that the embryos were good eight cell embryos. I was put on prednisolone 20mg daily from a week before E.T. this time and within 24 hours of starting them had developed severe vaginal inflammation. I was examined 48 hours before the transfer and given the antibiotics and ornidazole and flucanozole. I was also given a rectal suppository of indomethacin immediately after the transfer. Obviously I am very troubled as to why this cycle didn’t work and whether I could have done anything differently. My BMI has been between 24-26 over the cycles and I exercise regularly although my fitness is affected by the CRPS. I haven’t had any problems with endometrial thickness, it is always at least 12 mm. My uterus is tilted but I’ve been assured this wouldn’t affect anything. I have had one fibroid show up after a detailed ultrasound but I was told it is not in position that would cause problems. We have eight frozen embryos left in Cyprus but my husband and I are extremely conflicted about what to do. We have been advised by the clinic that they would leave our embryos to develop to the blastocyst stage this time and would also try physiotherapy to prepare my uterus for transfer. Our specialist is of the opinion that anymore tests or treatments would replicate the effect of steroids which I tried this time. We are very grateful to everyone who has helped us. After all this time, emotional trauma and expense it feels impossible to stop but also almost impossible to carry on. We would be enormously grateful for any advice you have. With many thanks. G and A.
A few questions please:
How old are you?
What region of the body does the CRPS affect?
Do you have recordable temperature changes? Oedema in the region?
Have you had your immune system checked?
Thyroid hormones normal?
Are you still menstruating? If so, how long or regular is your cycle?
Does an endometrial biopsy show normal development in the second half of the cycle?
Have you had a hysterosalpingogram?
Have you had a laparoscopy?
Dear Professor Winston,
Thank you so much for replying. Sorry I didn’t tell you how old we are! A and I are both 42. We have been trying to conceive since 2008 and have done seven IVF cycles over the last five years.
The CRPS is a result of a severe electric shock in 2006 and affects my limbs and particularly the palms of my hands and the soles of my feet. I was lucky in that I received intensive physiotherapy and as such the more severe physical consequences receded-but the intense burning pain has remained, as has the intermittent swelling and skin and temperature changes. I had a whole series of temperature and sensitivity tests that confirmed the diagnosis.
The only time I ever experience the pain anywhere else is always a few days after an embryo transfer when I feel like my womb is boiling (apologies if that sounds dramatic but it is the best description.) It has happened every IVF cycle and I believe was initially triggered by injecting that area in my first cycle. My CRPS specialist has never been able to offer a treatment. Last time it happened I went to my GP and he took my body temperature but it was within normal limits and there has never been anything I can do to cool it down-which is the case with the CRPS pain I experience. Apart from the skin looking red and flushed in my pelvic area there are no obvious external signs. The symptoms recede and then I either get my period or miscarry, depending on the pregnancy test result.
In terms of tests on my immune system would that have involved the routine tests at the Miscarriage Clinic? Nothing has been flagged up. The obvious problem is CRPS but this is not fully understood. The most recent research at the Pain Foundation by Andreas Goebel suggests that antibodies are involved and it is an autoimmune condition. IVIG treatment is still in the research stages.
The tests I had done at the Miscarriage Clinic in 2013 showed my thyroid levels were normal. I haven’t had the tests for Natural Killer Cells although we discussed it with our specialist. He didn’t think it was applicable and had always maintained that we just need the right embryo.
My menstrual cycle was always 28 days until after the IVF cycle in May last year when I had a miscarriage with the blighted ovum. My period after that was irregular, sometimes having a cycle up to 31 days. The last period I had signalled the end of our most recent IVF attempt two weeks ago.
I have never had an endometrial biopsy.
I had a hysterosalpingogram in 2010 in my initial fertility tests. I haven’t got the results to hand but I was told there was some scarring of my right fallopian tube but nothing else came up.
I haven’t had a laparoscopy.
We go to Cyprus as we wanted to stay being treated by our specialist in the UK but needed good donors which weren’t available here-he recommended the clinic there and performs the initial baseline ultrasound and any follow up when we return from Cyprus after the embryo transfer.
I’m sorry if I have answered in too much detail. We appreciate your time so much.
With many thanks,
This presents an issue which is unique in my experience. Given that I very foolishly thought I had seen everything in a longish career in one of the busiest European centres I feel very inadequate.
Firstly I have no experience with CRPS in connection with reproductive treatments. So I have no idea whether, as seems possible, your uterus is having some kind of argument with the embryo or with the minuscule trauma of the embryo catheter which results in rejection. If this was definitely the case though, I would expect you to have nothing more than a chemical pregnancy only. So I was wondering whether the normal inflammation set up by the pregnancy implanting triggers some curious cytokine response which then results in rejection of the pregnancy. All that sounds a bit like what Dr Goebel has told you. I agree completely with the people who have been treating you that NK cells are irrelevant, and would not be persuaded easily that immune therapy should be considered – like, for example, IVIG which has not been demonstrably effective on randomised trials.
What happens when you have an endometrial biopsy – do you get an intense reaction? and would the same apply when you had your HSG? Because, if not, I must say I think they are both worth doing. I know you had an HSG in 2010, but since then you have evidence of fibroid(s) and you could well have a fibroid in the uterine cavity which is distorting it – they grow quite quickly in 42 year old women and can certainly be associated with implantation failure. So I think a good HSG is worth repeating if you didn’t get a major reaction last time. The alternative might be an MRI but that would be more expensive and the hospital might balk at that. All the other tests which are commonly offered aren’t anything like as reliable. I am also curious about the ‘scarring of the right fallopian tube’ and a more up-to-date HSG may through light on its cause (as might a laparoscopy).
Whilst I am not in favour of immune therapy, if everything else is rigorously excluded, I agree that prednisolone given over the period of transfer and afterwards might be a good idea in quite high doses, possibly more than 20mgs – but this is not without risk and needs to be carefully discussed. I am reluctant to recommend this because the evidence that it is effective in IVF or implantation failure is very poor, but your history is very different and if some form of pelvic inflammation is triggered every time, it might be worth taking the risk. Also I slightly wonder whether injections of depot progesterone in large doses after embryo transfer continue for some time might be good. This is very much a trend in the USA. However such injections are painful and I am concerned this might provoke your CRPS.
The other issue which I have to stress is whether you should consider very carefully whether you should consider stopping treatment, going through a miserable period of grieving and bereavement, and a horrible sense of loss. All I can say is that proper bereavement with a firm intention of closing a door will in the long term very healing, even though it won’t feel like that now.
Please let me know your thyroid results if you care to, and also what you decide about the HSG. Also the biopsy might give a clue about the status of your womb lining. If you do have an X-ray, I would be happy to look at the pictures.
Very best wishes