Unexplained infertility
Dear Professor Winston,
My husband (34) and I (34) attended your seminar at the fertility Show in November 2014, which we found extremely helpful in raising questions in our minds about our own experience and prompted us to seek your advice. Over 3 years ago we started trying to conceive and in February 2012 I had an early suspected miscarriage (around 5 weeks). We continued to try to conceive unsuccessfully until March 2013 at which point we visited our GP for advice and some initial checks. My husband, who has had no previous paternities, produced a normal semen analysis. My periods are regular (approx. every 24-28 days) and ovulatory (approx. day 18) and my hormone profile is normal. In July 2013 I had a HyFoSy procedure, which indicated a partial bilateral tubal blockage. In November 2013 I had a laparoscopy and dye test, endometrial curettage and hysteroscopy. The consultant gynaecologist’s report was as follows: “On examination under anaesthetic I found her to have a healthy vulva, vagina and cervix. Saline hysteroscopy revealed a normal cavity with both ostia visualized. The endometrium was quite proliferative and there was a small polyp. An endometrial curettage and polypectomy has been performed. Laparoscopic findings showed a mobile pelvis with no evidence of endometriosis or adhesions. Both tubes were patent and filled and spilled rapidly. No pathology was noted… So far all investigations have returned as normal. I will suggest they continue trying to conceive on their own and we will see her back in the clinic if she is not pregnant in four months time. After two years of subfertility I will suggest they consider moving on towards IVF and this is something we can talk about in more detail if appropriate.” The histology from the endometrial biopsy returned as normal. While all this was obviously good news, it put us firmly in the category of ‘unexplained infertility’, which clearly brings with it its own particular frustrations. In March 2014 we had our follow-up appointment and were advised to opt for IVF. We were slightly surprised that there were no further tests prior to treatment but were advised that IVF would assist in any potential diagnosis. We subsequently underwent our first and only NHS funded IVF cycle in May 2014 fully aware of the prevailing success rates. Despite responding well (too well in hindsight as I experienced overstimulation) to the stimulation drugs with a collection of 10 eggs, only 6 were mature enough to use. Out of the remaining 6, 4 fertilized, 2 of which failed to develop beyond day two/three, 1 that was graded highly and the remaining 1 below par (we note your views on the grading of embryos). I had a day three transfer of the 2 embryos but unfortunately it was unsuccessful and I started to bleed before having a negative pregnancy test on 17th July. At our follow up consultation the consultant acknowledged that we are unfortunate to be non the wiser as to what is causing our infertility. He talked us through our failed IVF process and although “from the stimulation point of view [it] went well, demonstrating that [I] do indeed have polycystic ovaries” and that “it would have been more helpful if we had a large number of mature eggs and therefore a higher fertilization number.” For my next cycle he has suggested dropping my dose of Gonal F to 112 i.u (I was previously on a dose of 150 i.u), and proceeding with ICSI to see whether this will improve fertilization rate. We were advised that ICSI would aid a process of elimination as to whether it is my husband’s sperm that is not fertilizing the egg properly, or whether it is my egg doing something once fertilized – basically the failed embryos had ruptured so there is a question mark surrounding this. After listening to your views regarding ICSI we are unsure as to whether we would want to proceed with this or whether it is even necessary. The clinic suggested us starting our next IVF cycle in October/November 2014, but we have not yet proceeded. After our failed IVF cycle in mid July 2014 I had my next menstruation 41 days later on the 24th August. On the 25th September I unexpectedly had a positive pregnancy test! My husband and I were somewhat stunned that we could have conceived naturally after the rollercoaster of events over the last 2.5 years. We were relieved and extremely happy, although aware that this did not necessarily mean we would have a baby. I was advised by both my GP and IVF clinic to have an early scan, which we had privately at 6 weeks. All looked normal, my endometrium was thickened, measuring 24mm in A.P. diameter, and a possible intrauterine gestation sac was seen but because only an abdomen ultra-sound was performed it was not possible to check viability of the pregnancy. Sadly, I started to bleed at 7 weeks and had a complete miscarriage. The histology report confirmed that the pregnancy had been in the correct place so along with the fact that we conceived naturally we were told this was positive news. The consultant gynaecologist who saw us at the hospital believes that given my two miscarriages, failed IVF, length of time trying to conceive alongside my age and being medically fit and well (although I have asthma I do not smoke, barely drink and my BMI was 20/21 when last checked prior to commencing IVF) that this warrants further investigation to determine whether there is anything inhibiting my ability to carry a viable pregnancy. Although we were extremely sad to have lost this pregnancy we welcomed the suggestion for further investigations and felt it would be a positive step. In February 2015 we had tests completed for recurrent miscarriage (Fsh, Lh, Testosterone, Prolactin, Lupus anticoagulant, anticardiolophin antibodies, full thrombophilia screen, Factor V Leiden, Prothrombin gene mutation, Chromosome analysis – karyotype, Amh). The results revealed that I am Factor V Leiden heterozygous. All other results were fine and my AMH result was 26.9. Although we were told what my care would be if pregnant, we now find ourselves with unanswered questions and uncertain how best to proceed in terms of our ongoing difficulty conceiving. Does FVL impact your ability to conceive as well as maintain a pregnancy in some cases? Do we go ahead with a second IVF cycle? Or, would it be advisable to continue trying to conceive on our own for a while? Should I consider taking a low dose of aspirin? I have previously wondered whether I may well have fallen pregnant naturally within 8 months following the laparoscopy – that perhaps the polyp was prohibiting falling pregnant previously and the IVF cycle may have even hindered rather than helped the process. However, I have since wondered whether my short luteal phase alongside FVL is the issue, given that we last conceived during a longer than normal cycle. We are feeling at a total loss in terms of who to turn to for advice. Obviously we would rather conceive naturally and loathe the idea of having further treatment that may be unnecessary, particularly given the financial burden. However, the fact I will be turning 35 in 5 months is a concern for me, but at the same time I am cautious about committing to another IVF cycle after experiencing first hand what a physically and emotionally grueling procedure it is. Your advice and guidance on where we go from here would be extremely helpful. With thanks & best wishes M
Dear M,

May I direct you to something I wrote about a little while ago?

In recent years a great deal of research has gone into the medical management of unexplained infertility and it is clear, from various studies, that in many centres around the world, there is much overtreatment. That is to say that many of the regular methods of helping people with unexplained infertility are quite unnecessary.

Over 20 years ago, two colleagues Patrick Taylor and John Collins wrote a detailed account of the subject in their book ‘Unexplained Infertility’, now sadly out of print[1]. In a book of over 250 pages, they wrote what I consider the best account of unexplained infertility ever written. Whilst showing huge sympathy and great sensitivity towards couples with this ‘diagnosis’, they gave a detailed mathematical analysis. They evaluated the likelihood of getting pregnant when, after careful diagnosis, this condition was treated by various means including IVF. What they showed was that most of the treatments that had been used had not been properly compared with no treatment at all. In essence what their book reports is that virtually all treatments that are used are no better than doing nothing. I can do no better than to quote the last paragraph of their penultimate chapter:

“….on the issue of efficacy, however, only clomiphene therapy has been demonstrated by means of acceptable clinical evidence in the form of randomized trials as a treatment with proven superiority of no therapy. On the basis of best available evidence, HMG (gonadotrophins) plus intrauterine insemination has possible but unproven benefit, and no studies exist to demonstrate a benefit for in vitro fertilization methodology”.

Over twenty years later, their position certainly seems to be still justified. Dr Fleur Kersten from Nijmegen in Holland and her colleagues have just published an important study on this subject two months ago[2]. They collected records from 25 clinics and identified 544 infertile couples who had been carefully examined and who had no clearly identifiable cause for their infertility. The average length they had been infertile was 1.5 years. The patients they define as having unexplained infertility included a number who only had one tube clearly open, some had mild male infertility (motile sperm count ranging from 3 – 10 million) and some mild endometriosis. Any female patient over 38 was excluded.

Of these 544 couples, 198 had had what Dr Kersten called overtreatment – that is, within six months of presenting with infertility they had had ovarian stimulation or IVF. 346 couples had no treatment but were simply followed expectantly for one year. In the treated group, 28% got pregnant within six months of starting the survey and in the untreated group 31% had a pregnancy. After one year, 42% in the treated group got pregnant and in the untreated group 41%. Eventually, 90% of the treated group had a pregnancy compared with 91% in the untreated group who had a pregnancy naturally.

I find this study not only interesting, but also, in a curious way extremely reassuring. Firstly the authors point out that treatment often seemed to delay the much wanted successful outcome. Secondly, some mild causes of infertility – for example, an apparently rather low sperm count do not condemn anxious couples to a life of sterility. Thirdly, it is very clear that after thorough testing and a diagnosis of genuinely unexplained infertility carefully diagnosed, there is an excellent chance of having a pregnancy naturally without expensive treatment. Perhaps the message should be – ‘just think of the number of women who have got pregnant spontaneously after several treatment cycles have failed’.

Incidentally, I doubt whether the Factor V Leiden test is relevant, and I am suspicious of many these tests for ‘failed’ implantantation. I would like to see a hysterosalpingogram and would like to be sure you and your husband have had a karyotype done on enough cells to make certain neither of you have a chromosomal problem, but I suspect those will be normal. Getting the analysis done on a good number of cells may be important because you may be mosaic – some normal eggs, some abnormal ones. As to another IVF cycle – well, you have 25% chance each time……

Best wishes
Robert Winston

[1] Unexplained Infertility by Patrick J Taylor & John A Collins, Oxford University Press, New York and Oxford, 1992.
[2] F.A.M. Kersten et al. Overtreatment in couples with unexplained infertility. Human Reproduction 2015 Jan;30(1):71-80

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