Aneuploidy as a cause of recurrent miscarriage

My RE sent me a study on aneuploidy (=abnormality in chromosome number) as a cause in recurrent pregnancy loss, and it was a fascinating, yet difficult to grasp read, as far as significance went.

They started with this statistic -- the prevalence of fetal aneuploidy in women in sporadic miscarriage (ie have loss(es) interspersed between live births) is around 76%. In women with recurrent loss, it is much lower-- around 50%.  This means that with recurrent loss, there is possibly greater contribution of factors other than a genetic abnormality in the embryo. Yet, fetal chromosmal abnormality still prevails as an important cause---around 50%.

They then subdivided by the patients based on presumed issue, such as as anti-phopholipid syndrome (APS), uterine abnormalities, abnormal karyotype in either partner, hypothyroidism/Diabetes/PCOS and then looked at incidence of fetal chromosomal abnormalities.

As expected, when either parent had a abnormal karyotype, they produced a very high number (over 75%) of aneuploid embryos.The APS and hypothyroidism/Diabetes/PCOS groups held steady with around 50 % of examined embryos being aneuploid. The uterine abnormality group had a much lower percentage of aneuploidy, around 17%.

The point the authors made conclusively- aneuploidy is a significant, but not sole,contributor to pregnancy loss, even of the recurrent variety.  But here is the question I want answered---do certain conditions or gene mutations predispose to a higher rate of aneuploidy?We all know advanced maternal age increases aneuploidy. However, the average age of women in this study was 32 years.  What are the other factors?  Does PCOS, for example, make the mother more prone to producing aneuploid eggs? Or do they just have 2 separate issues (the second of which-- the cause of the aneupolidy) is unknown?

I've done many pubmed searches trying to link issues found in me (such  PCOS, PAI4G and the MTHFR C677T) mutations and increased aneuploidy.  Turns out, there have been people trying to study the same.

The only semi-tangible thing to show up is the folate connection. The MTHFR 1298C mutation (but not the C677T) mutation has a link to an increased incidence of fetal aneuploidy. Interestingly, multiple other studies have reported the same, they see an association with the 1298C but not the C677T mutation and various single chromosome aneuploidies.

Furthermore, many, many studies show that low folate levels increases chromosomal abnormalities in cells of the immune system.  But what about germ (sperm and egg) cells?

A smart study looked at the effect of folate supplementation on aneuploidy in sperm (something that is so easily studied!), and basically found that increased folate intake decreased sperm aneuploidy. 2 important things: folic acid could possibly decrease risk of aneuploidy in eggs as well, and women, make your husbands take that 5 mg dose!

BUT--- whatever the road to it, aneupoidy is a major contributor to pregnancy loss. One statistic that knocked the carpet out under me was the finding that 40% of all IVF-generated embryos (even in younger women) are aneuploid. Is this true even of the natural process?  Is that why so few natural tries end in a clinical pregnancy?

I was recently pointed me to this study by a couple of people (thank you!)---Super-fertility’ may explain some miscarriages, BBC News has reported. It says that the wombs of some women are ‘too good at letting embryos implant’, even those that are of poor quality and so which should be rejected.   

Basically, if you take the assumption that the natural rate of aneuploidy is as high as that in IVF, and combine it with the above study, then, well, that would explain a lot, including what happened with me. Heck, maybe my aneuploidy rate is even higher than 40%, but my uterus is a champ at implanting any and all comers.  Or not. Who the heck knows?

Preparations..

Thank you all, everybody who responded to my last post, especially the final comment on surrogacy.

I've been a terrible blogger, so much so that I have not even been reading all the blogs on my list. As far as life goes, I feel like I'm on a treadmill I can't get off, I'm running, but am making little progress.

To catch you up on the TTC journey, a bullet list may be best

• If we can, we will go with CGH microarray for all generated embryos. Our only viable candidate for testing looks like it may be Bluegnome, based out of England, that offers this test for aneuploidy testing.  Bluegnome has developed the technology and is trying to distribute and train labs all over the world to use it. Here, there is the question to be pondered : I can try to ship frozen biopsy cells to England, or to somebody who now offers this test in India, an embryologist in Delhi.  Obviously, it would be far easier and cheaper to send the cells to Delhi, as opposed to shipping to England. But, I'd feel more secure if somebody who had done this test a gzillion times before does it. But then, this technology has been designed in such a way that using it, and obtaining interpretable results is easy. The scientist in Delhi has gone and trained at the Bluegnome facility in England.  Bluegnome's Indian partner offered me both options, but strongly pushed the Delhi choice. I have not decided what to do yet- right now, as long as I can test the embryos, I will rest relatively easy.
• I met with my doctor and got the details of the IVF protocol which will be used in my case- 3 days of suppression, using Lupron (a GnRH agonist), CD1-CD3,  followed by starting menagon (which is a mix of FSH and LH), on  CD3-9 (I think it ends on day 9). This was a very pleasantly short protocol, and I hope it works for me.
• I met with the lawyer to take the first first step of the surrogacy process. I want to recruit 2 surrogates, with a single embryo transfer per surrogate. Since I will be freezing the embryos down, this should be logistically simpler. I'm totally ok with ending up with 2 kids, as long as they did not undergo the risks that come with a twin pregnancy. I'm getting 2, because I fully anticipate that atleast 1, or both of them will fail, and I just want to move this process fast.
• I started metformin.I'm entirely unsure if I need it, but right now I'm going to go with the empirical method. I'm been on it for around 4 days now,  at a 1000 mg for the past 2 days. Apart from a slight headaches (god help me if I skip or even delay any meals) and the mildest of heartburn, no side effects at this dose. Interestingly, I've been having issues with acne (mostly on the body, rarely on the face), but both seem to be subsiding after I started it. I'm  contemplating going up to 1500, but the headaches are off putting.
• I've also finally started a high dose (5 mg) of folic acid. Since my homocysteine,which needs to be cleared either by folate or vitamin B12 had been low(and still was), I had never considered that therein lay a possible issue, but it may well have been, since I have one copy the C677T mutation. Note: The reason my homocysteine was not high may be attributable to my extremely high vitamin B1-2 levels. Everybody is worried about high folic acid supplementation masking a B-12 deficiency, I wonder if I had the reverse issue.
•  I have to get the swimmers shipped. While I still want to try with the donor I've used in the last tries, I'm wondering whether I should ship another donor, as backup if need be. But its so very hard for me to actually decide on another donor, lets hope I can find somebody else I feel comfortable with.  Also, lets face it, at this point, its all a game of russian roulette. My donor has been excellent at getting me pregnant, and seems to be very, very good with hordes of other women, none of whom have had issues with pregnancy loss. A new donor would be a completely unknown entity.

So much is being done, such drastic measures are being taken and yet, when I think of my chances for actually succeeding in all this, I have to be honest, I've lost all faith that anything will work. I think that is because I still can't understand why things have failed, over and over. How can they have failed? Will this trend ever reverse?

Is it my biology? Is the issue in my eggs, manifesting in a high rate of aneuploidy?I've got a big, speculation-filled post brewing in my head about the many roads that can lead to an increased rate of aneuploidy, which appears to be a prevalent cause of pregnancy loss. Good, if complicated paper on the subject, I'm still trying to fully understand it. Post coming up if I succeed.

It also comes down to faith. Does the universe not want me to succeed right now, not because it wants to punish me, but because it has an alternate plan for me? I honestly don't know anything anymore. 

I want to do IVF the next cycle- since I'm CD2, that is approximately 30 days away.  Exciting, yet terrifying times!