The more I learn; the less I know...

The morning after our most recent BFN, I woke up with my arms and legs feeling sore from Cross-Fit, and my head was slightly throbbing from drinking a bit too much wine. As I've done on prior occasions, I had a moment of wondering if my negative results were part of a dream. Maybe I didn't actually test yet and there was still a chance... "Well it's another day, another failed IVF transfer" Husband announced to pull me out from under the fog of my hangover. As the kettle started boiling water for some much needed tea, I sat down with The Google and typed the words 'recurrent implantation failure'.

I found a rather comprehensive review article that was published in Reproductive BioMedicine in 2013. The author began by noting that there still is not a universally accepted definition on what constitutes Recurrent Implantation Failure (RIF), but for the purpose of her article, she included any women under the age of 40 who fails to achieve a clinical pregnancy after 3 fresh or frozen transfers with 4 good quality embryos. So, I'm not sure if I meet that criteria, but I decided to continue reading as she defined that treatment should focus on improving embryo quality and endometrial receptivity.

Regarding embryo quality, she cites that only 30% of embryos will implant. I am presuming this is a global average, as it doesn't account the higher success rates with donor eggs, but we all know that implantation rates with donor gametes will only reach 60-70%. She also noted that as embryologists select the best embies first, lower success rates can be expected with subsequent transfers as the embryos will be of reduced quality. Rather disheartening to see that in print. It's also humbling to accept that despite the top grade and euploid status of my embryos, they may have quality issues. Nonetheless, this is what we have with which to work.

Uterine factors can include congenital findings such as a septum, (been there, fixed that) or acquired pathology such as a fibroid, polyp or adhesions. The presence of fluid in the fallopian tube, a hydrosalpinx, can negatively impact the endometrium and make it unfavourable for implantation. Pregnancy rates are improved once the tube is isolated from the uterus, which creates the irony that fertility is enhanced by sterilisation. She deferred the issue of immunologic factors by commenting that it's "an interesting area worth a separate in depth review" and summarised that there is no consensus on whether or not immunological investigations and treatments are useful. Somewhat similar, some studies have demonstrated a benefit with thrombophilia evaluations and appropriate treatments, while others have not.

The work up should start with a sonohystogram and/or a hysteroscopy. A hystersalpingogram is more sensitive than an ultrasound for detecting a hydrosalpinx, and any suspicious findings warrant further evaluation with a laparoscopy for possible intervention. Regarding the management, she describes "a multidisciplinary  approach should be adopted (interesting word choice) between an experienced fertility specialist, senior embryologist, reproductive surgeon and counsellor. This appointment should not be another 'routine' review." Regarding lifestyle factors, it's not surprising that the data finds smoking is bad, a healthy weight is good and alcohol intake should be limited to 1-2 drinks per week, if at all. Routine use of assisted hatching is not supported by the American Society for Reproductive Medicine (ASRM), but the author reports that it may benefit those with a poor prognosis or two or more failed cycles. The transfer procedure itself should be performed with ultrasound guidance, and a procedure that takes longer, invokes cramping, and requires changing multiple catheters or uses a tenaculum is associated with lower implantation rates. Good to know. I did take note that she did not address increasing the number of embryos at transfer.

Selfishly, I skipped the section on the thin endometrium, as actually, I am starting to wonder if my lining is too thick. More so, I question if my normal appearing endometrium is functional. About ten years ago I met Dr Harvey Klinman, as he presented his recently published article describing his method for testing cyclin E and p27 as a measure of endometrial competency. XYZ Fertility Centre (the site of my embryology lab) lists the Beta-3 Integrin test as a measure they employ (this analysis is also used at CCRM). When I previously asked my RE about Klinman's endometrial function test, he replied that the data isn't consistent. Some patients who lack said markers are able to achieve a pregnancy and others with the proper components still can't become pregnant or continue to miscarry. My case is interesting as I have been pregnant twice, although with the first, my uterus rejected the pregnancy rather early (I attribute my septum as the cause) and the second was due the trisomy, but we'll never know if I could have maintained that pregnancy if there had a normal set of chromosomes. Regarding the action of an endometrium biopsy, the process of inducing an injury and causing a release of cytokine did double pregnancy rates in a trial published back in 2003. This begs the question, do I undergo another scratch?

Based on his voicemail message, I have the feeling my RE is going to steer me in the direction of transferring two embies next time. I'm starting to accept that it's more likely to result in a waste of two normal embryos, than a twin pregnancy, but I've still seen this move too many times before. Couple fails single embryo transfer. Couple transfers two embryos. Boom. Twins. Plus, these are two grade 1 euploid embryos! I needed data, so I googled 'twin rates with two euploid embryos'. My search brought me to two articles that compared a single transfer with an known euploid embryo versus two untested blasts. The first study described that 39 singleton pregnancies were achieved with 60 women doing a single transfer in a fresh cycle (65%). 43 pregnancies were noted in the 61 women who transferred two blasts (70%) but 24 were singletons (55%) 18 were twins (42%) and there was one set of triplets. They also looked at women doing a frozen transfer, and found 15 single pregnancies from 27 women with single euploid transfers (55%) and 13 from 25 women with a double transfer (52%). The 13 pregnancies included 5 singletons and 8 twins.

The second study included number of days spent in the Newborn Intensive Care Unit (NICU) as one of their endpoints. Not surprisingly, they found that the twins born to couples who were in the two unknown blasts group had a five fold increase in NICU stay compared to the singleton babies born to women in the single euploid embryo intervention. (actually there was one baby in the singleton group who was in the NICU for over one hundred days, if he or she were excluded as an outlier, I think the ratio would be more than ten-fold.) The authors concluded, "enhanced embryo selection with a single euploid embryo was associated with high reproductive potential without compromised delivery rates and improves chances for a healthy term delivery after IVF." Dude, you're preaching to the choir... I still wasn't finding answers about transferring two euploid lasts, so I searched a little more an uncovered another article that was also comparing a single euploid blasts versus two unknowns. The author admitted that their study design initially included transferring two euploid blasts, but it was associated with an "unacceptably high twin risk." I'm presuming that intervention group was stopped early. Of course, the participants in these studies are IVF virgins, not three time losers such as myself.

Next, I took a look at the 2013 ASRM guidelines for the maximum number recommended to transfer, and noted that they do not specifically address euploid embryos, but they do make a distinction between "favourable" embryos and "all others". Presumably, my euploid embryos would fall in the 'favourable' category, but when I read the fine print of the foot note "favourable" was defined as "first IVF cycle, good embryo quality, excess embryos available for cryopreservation, or previous successful IVF cycle." So now I'm not sure if I'm considered 'favourable' or 'all others'. Anyway, for women in my age group, they recommend a maximum of  2 favourable blasts and 3 all others. Then, I saw a note that one additional embryo may be added to all age groups and all situations when a patient has two or more previous failed fresh cycles, or a less favourable prognosis.

That word fresh is the distinction. Technically, I haven't failed a fresh cycle. My RE admitted he didn't have any explanation as to why I scored with a fresh transfer, but failed with two frozen embies. Theoretically, conditions for implantation are more ideal with a frozen transfer. I revisited this notion with my RE when he called with my day 5 embryo report. He didn't feel a fresh transfer was indicated as my fro-yos had thawed well, and the risks for OHSS were too high. Yet, things aren't always what they seem. Maybe I could consider a minimally stimulative IVF cycle to gain a few embryos that could be employed in a fresh transfer.  Of course, this also involves surrendering any benefit from CCS testing, as well as sacrificing a single embryo transfer. Grrrr! 

I felt more depressed and discouraged after researching recurrent implantation failure, than I did after reviewing recurrent pregnancy loss. Unless, I happen to have a hydrosalpinx which could be clipped, there really isn't an identifiable explanation. Maybe, it's just as simple as I've just been really, really, really unlucky and the next one magically will work.  Oddly, I've been thinking about a clip from an interview with Jaime Foxx at the time of the premiere of his movie Ray. He described that while preparing for the role, he played with Mr Ray Charles and noted that during one session he became angry when Jaime missed a few notes. "Son," Jamie recalled him saying very sternly, "The right keys are underneath your fingertips. All you have to do is find them!" The actor felt that what Mr Charles was really trying to teach him, was that in life the right choices, the right directions are already there in front of us, and we just have to find them. So begins our quest: the right formula is out there -we just have to find it.