What is the long term outcome for couples with recurrent miscarriage?

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…or “Why genetic anomalies of embryos are more likely to be important than taking steroids”

I’ve been very lazy with my blog lately but have decided to use my recent trip to the international conference ESHRE in Stockholm to give you some feedback about current activites.

One study that caught my eye was a Danish study that looked at the outcomes of couples who had had at least three early pregnancy miscarriages and how often they will ultimately go on to have a live birth.

The study was very encouraging. It suggested that around two thirds of couples who had had at least three miscarriages will ultimately go on to have a live birth, but this can take many years. There is also a significant impact of female age, in that as women are getting older (particularly into the early 40s) there is a lower chance of a successful outcome. This is probably because the miscarriages at that point, are overwhelmingly due to poor/older eggs.

A couple of things come to mind about this study. Firstly it is vitally important that appropriate investigations are undertaken for repeated miscarriage. This includes checking that the woman does not carry a particular blood clotting problem or endocrine disorder, that there are no subtle infections or anatomical problems of the uterus, and further, that there are no karyotype (genetic issues) carried by either partner. At Sydney IVF we also look very carefully on the male side, not just for sperm numbers and motility (these simply lead to infertility) but high rates of DNA fragmentation of sperm can also lead to miscarriage without necessarily reducing implantation potential.

One of the challenges that doctors have is that in at least 50% of cases of couples with repeated miscarriage, no identifable cause will be found. This is probably because there are lots of occasions (in both natural conceptions and in IVF) where embryos have the correct ability to implant but not the correct genetic programming or development to continue beyond the first few weeks of pregnancy. This is a sad but inevitable part of human biology. If you think about it, it’s surprising that anyone can achieve a successful pregnancy at all, given the complex relationships between sperm and egg that have to occur to achieve this.

However, because a good 50% of people with repeated miscarriage will not have an obvious cause, my concern is that this leads to lots of “new diagnoses” coming along. As fertility specialists, we have to carefully evaluate whether such causes are real or whether the issue is really simply one of any individual pregnancy just not having the right developmental ability to continue:  that is, just a case of back luck on that occasion. A common situation that emerges is the question as whether some women carry implantation disorders due to immunological changes in the uterine lining. This has attracted a lot of attention over recent years (I’m talking here about the measurement of natural killer cell levels in the uterine lining or in blood) and because the situation sounds very attractive, this testing inevitably gets performed very regularly. However there have been very few well conducted trials to show that natural killer cell activity actually leads to miscarriage and certainly no clear proof that the problem leads to reduced implantation at IVF. It is also a situation where the test results themselves are not well validated and that means that a so called “abnormal” level may not actually be abnormal. We still need to do a lot of work in developing the reference ranges and the true significance of these tests.

The problem becomes more compounded whereby if a couple are given a diagnosis in this area, the woman then inevitably gets commenced on medications that can have a potent impact on her health. In other words we may end up treating something that doesn’t really exist and all we are now doing is adding potential side effects to the woman and perhaps some higher risks to pregnancy as a result of these medications. I’m talking here about the use of corticosteroids.

Which brings me back to the Danish study. Perhaps if we just simply ensure that the proven causes of miscarriage are not present in couples, we can encourage them to continue attempting conception with confidence with the expectation that two thirds of them will achieve a successful live birth without adding in fancy or potentially problematic therapies. However, the Danish study did follow people out for several years, and time can be the biggest challenge. To that end, given that many repeated miscarriages do involve random chromosome errors of embryos, if time is getting on then genetic testing of embryos within IVF would appear to have a role. It is important however that this technology is applied appropriately and that the most accurate and up to date assessment is undertaken. This involves preimplantation genetic testing of embryos with the use of comparative genomic hybridisation, or CGH. Using this technique, embryos can be screened and at Sydney IVF we have Australia’s biggest experience in this area.

The genetic testing of embryos however requires accurate high tech equipment and testing techniques do vary form unit to unit. At Sydney IVF we have clear data to suggest that the testing of embryos at a later stage (the day 5 or blastocyst stage) has the mininum effect upon an embryo and the maximum chance of the subsequently transferred embryo leading to a successful pregnancy. For more information on this you can see the Sydney IVF website and in particular discussion from our Scientific Director Steven McArthur, who is a world leading expert in that area.

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