Dear Professor Winston, I am 32 and have PCOS. My husband has low sperm count. We are receiving treatment. We have had 2 fresh cycles, one which ended in a chemical pregnancy and 2 fet, one which ended in a miscarriage at 7 weeks. We have 2 frozen blastocysts still to transfer. At our recent review meeting the doctor said the results are very worrying as we are getting good quality blastocyst, yet they are failing to progress. He has advised that we may want to do the immunology tests through Care which cost £2000. I had been researching these on the web, but I am unable to come to a conclusion on their credibility. Any advise on these would be fantastic or any other avenues you think we could explore. I just want to to congratulate you on your resent presentation at Science Live. We took some students from our school and they really enjoyed it. Regards, M
Dear M,
You should not be sending emails at this time of night, but should be tucked up in bed! I shall suggest to our web administrator that we do post your email to me on the website because you raise important issues, but I shall take the precaution of deleting the name of the clinic you mention where you have been treated.
It seems pretty incredible that you could have three separate, unrelated causes for your infertility – PCOS, a sperm problem and also an immune problem. Assuming you have had an HSG to confirm your uterus is normal (an abnormality there is much more likely to be a possibility than any rare immune problem) and just possibly (but even less important) chromosome tests to make certain you have no obvious genetic cause for your problem which may affect any embryos, I disagree strongly with the advice you have been given.
Treating imaginary immune problems in the absence of really good evidence that these exist in your case, is simply not a good idea. And you are quite right, there is very little credibility in these claims and in my view that it is wrong to charge £7000 for a purely experimental treatment. I have no objection to your having such experimental treatment providing a) there is no serious risk to your health, b) no serious risk to the health of any pregnancy and c) properly informed consent by you and your husband and lastly d) providing you do not have to pay for it. But it seems immoral in my view to charge for a treatment simply because it is available when I know of no randomised controlled trials which show the slightest benefit to what this clinic seems to be proposing. Actually, I am shocked that the HFEA, the regulatory authority to which you have to pay a fee to regulate your treatment, does not clamp down on this.
Look on the bright side. The statistics suggest that the fact you have had two pregnancies, however early, are eventually in favour or a successful outcome eventually, though possibly not with the blastocysts you have in store. My advice would undoubtedly be to have these transferred – and if you don’t trust this clinic, you may wish to consider asking them to transport these blastocysts to another centre. I also have to say that, in the long term, a great deal is likely to depend on the quality of your husband’s sperm count. If it is not too bad (you don’t tell me whether fertilisation was natural or whether ICSI was necessary) you have probably quite a good chance of a successful pregnancy without treatment, or possibly with a bit more persistence with stimulation of ovulation.
Sorry to give you such a robust reply – but I guess you might have expected this having had to sit through one of my lectures.
Good night,
My best wishes to you and your husband,
Robert Winston
Dear Professor Winson,
Thank you so much for your reply. I didn’t expect one so soon, especially not one so late and over Christmas.
You have put my mind at rest and saved me lots of hours reviewing immunology tests on the internet. We will no longer be having them. I have not had a HSG test so I will ask about this at our next review.
Sorry, I didn’t give you that much information before. Our first ICSI cycle was long protocol. I produced 14 eggs, 11 were mature and 10 fertilised. Three made it to day 5 blastocyst, but they said they were very early stage. We transferred one and froze one of the other two on day 6. This ended in a negative result and the frozen cycle was a 7 week miscarrige.
We had basic immunology tests on the NHS and a chromosome test which didn’t show any problems. Our second ICSI cycle was short flare with cetrotide. I was also prescribed metformin for my pcos. I produced 11 eggs and 10 fertilized. We had three day five blastocyst and one day six. We all so used the embryo scope, I had an endometrial scratch, and we used embryo glue. This resulted in a chemical pregnancy. Our fet ended was negaitve. I did have trouble with the endometrial lining thickening this time. It measured 7.8 mm before we were sent for transfer, but my elleste solo 2mg tablets were increased to 7 tablets a day.
We have two frozen embryos left. The doctor mentioned if we have to go for another fresh cycle we may be best to do Array CGH with ICSI. What is your view on these and do you think it is advisable in our situation? He also mentioned that I need to put on weight as my BMI fluctuates between 18 and 23 and this could be causing implantation problems. I am tall and do have a balanced died but I have been trying to eat more.
Thanks you so much for your advise. It is invaluable to have when you are in such a vulnerable situation.
Regards, M
Dear M,
One thing that comes out of your letter is that you were told these were ‘very early stage’ blastocysts. Well over 25 years ago, our research clearly showed that not all blastocysts have equal potential for further development. In particular, Dr Kate Hardy in the Genesis Research lab, working with Sophie Spanos and one or two others, showed that some embryos which developed to the blastocyst stage had far fewer cells than would be expected at day five. So I am wondering whether this could be true in your case. What the embryologist may be seeing – there is no way of easily checking without destroying the blastocyst – is a reduced embryo with perhaps half the normal number of cells – say 60 rather than 130 or so. So it is quite possible that the blastocysts you have stored are of not the best potential. That doesn’t necessary mean they cannot result in a successful pregnancy but it would lower the chances. If transferred there is no risk of an abnormal baby – that has not been reported. As to array CGH and ICSI, I am very unconvinced. Firstly, I would not dream of trying to biopsy these embryos when they are thawed. If they do have reduced cell numbers, taking further cells away is going to make them even less likely to implant. At this stage of your treatment, I think I would consider just have these embryos transferred providing the endometrium looks in good condition. But see below ……!
With regard to CGH and ICSI in a future cycle, I am very unclear why this is suggested. It seems a bit as if the team who are treating you are thrashing around for an answer – one moment you have an ‘immune problem’ which means trouble with the uterus. Now you are being told you have something diametrically opposite, a ‘problem with the embryo’. And as for ICSI, do you also have such a problem with the sperm? It does not seem to make much sense to me. In any case, with regard to CGH, there are no randomised controlled trials that this improves pregnancy rates. Indeed, a paper by Dr Mastenbroek from Amsterdam (I enclose a summary abstract at the end of this email) suggests that embryo biopsy, needed for CGH, may reduce the chance of a pregnancy by 50%. Now I do understand that this study he has done applies to preimplantation embryos, not blastocysts, but so far nobody has shown a convincing difference on a randomised basis. Also, they admittedly did not assess trials with preimplantation genetic screening by CGH as this was not widely available then, but I am most unconvinced it would be substantially different. Don’t forget that it was our group which invented embryo biopsy, so I do feel a bit qualified to look at this process with a slightly different eye.
What I do find rather disappointing is that you can be offered all these high tech expensive treatments, but a basic work up of the cause of your infertility is clearly quite incomplete. I really do not want to undermine your confidence, or the confidence in the team treating you as I am sure they are acting in good faith, but I do get the feeling that there is an emphasis there on the latest technology without sometimes thinking about basic physiology.
You have clearly been told at least one thing which sounds eminently sensible. Your BMI is low, and a bit more body fat would be healthy and could improve ovarian function. I cannot help thinking that if you did that and were able to ovulate normally, you would get pregnant naturally. And if not, your response to ovarian stimulation and IVF would be much improved, and you would then have embryos of significantly better quality. Oh, and by the way, get that HSG done by a competent radiologist – and get to bed a bit earlier, in future.
Here is the abstract of Dr Mastenbroek’s et al. interesting paper “‘Preimplantation screening: a systematic review and meta-analysis of RCTs’, Human Reproduction Update, 2013, 206
Abstract
BACKGROUND:
Preimplantation genetic screening (PGS) has increasingly been used in the past decade. Here we present a systematic review and meta-analysis of RCTs on the effect of PGS on the probability of live birth after IVF.
METHODS:
PubMed and trial registers were searched for RCTs on PGS. Trials were assessed following predetermined quality criteria. The primary outcome was live birth rate per woman, secondary outcomes were ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate and pregnancy outcome.
RESULTS:
Nine RCTs comparing IVF with and without PGS were included in our meta-analysis. Fluorescence in situ hybridization was used in all trials and cleavage stage biopsy was used in all but one trial. PGS significantly lowered live birth rate after IVF for women of advanced maternal age (risk difference: -0.08; 95% confidence interval: -0. 13 to -0.03). For a live birth rate of 26% after IVF without PGS, the rate would be between 13 and 23% using PGS. Trials where PGS was offered to women with a good prognosis and to women with repeated implantation failure suggested similar outcomes.
CONCLUSIONS:
There is no evidence of a beneficial effect of PGS as currently applied on the live birth rate after IVF. On the contrary, for women of advanced maternal age PGS significantly lowers the live birth rate. Technical drawbacks and chromosomal mosaicism underlie this inefficacy of PGS. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice.”
Warmest wishes
Robert Winston