Breathing easier

As I sat on hold with my health insurance rep while waiting to board the plane, an incoming call came. I knew that area code meant there was no letting this one go to voicemail. I hurriedly asked to put him on a brief hold, turning the tables on my insurance company, to get the news. The "good news" was quickly passed along—two euploids, a low-level mosaic, and a high-level mosaic. And so, yet again, I found myself in a space for which I hadn't mentally prepared. I was waiting for the euploid/aneuploid break-down. I knew mosaics were unusual. And now we had two??

Two more euploid embryos! And some... mosaics? It's time for another dive into the medical literature.

I dove in and quickly surfaced with one fun fact: mosaicism happens during early cell divisions as the embryo is developing. In other words, this issue stems from neither my eggs nor Nicolas's sperm. So, one point for these aging eggs—I'm now 6 embryos deep into pre-implantation genetic testing and haven't yet come across a faulty egg among the day 6 survivor cohort. It's nice to feel like I'm not entirely broken and withered out and generally past my prime. But feelings won't help me understand what's left in the freezer, which is just where you'll find my low-level mosaic—Spring informed me that she can be considered as a back-up. A what now?

Our testing facility labels embryos as low-level mosaics if 20-40% of the biopsied cells were found to be abnormal. In other words, this girl's trophectoderm (the bit that would become the placenta) is 60-80% okay. When a small sample of cells taken from that far away from the future baby's body are for the most part normal, odds are that a baby born from this embryo would be chromosomally normal too. 

Mosaics are categorized by a few things:

• What fraction of cells were affected?
• How many chromosomes were impacted?
• Is it a whole chromosome issue or just a segment of one?
• What cell type is affected—inner cell mass (future body), trophectoderm (future placenta), or both?

In our low-level mosaic's case, we've got the best possible answer to the first of these three: just 20-40% of cells were affected, only one chromosome is at play (chromosome 5), and only a segment of that chromosome was duplicated. As per the final question, only the trophectoderm got biopsied, so we can't answer that. To the extent that we can evaluate this embryo, it's as good as they come in the world of mosaics. Per the medical literature, "[low-level mosaic] embryos have equivalent developmental potential as fully euploid ones." Put that way, it kind of sounds like we just got 3 good embryos.

A recap on our standing after cycle 3: we've got ourselves 4 (or 5) embryos graded as shown here.

So what's next? We already had to pull the trigger if we hoped to squeeze in one last cycle before this summer's Eurotrip. That trigger got pulled. My next—and now, final—surgery is scheduled for mid-to-late July. As it stands, we have a 93% chance of a live birth without even counting our low-level mosaic. It's time to call a wrap on these medical hurdles and cringe-worthy bills.

I don't want to count our chickens before they're hatched, but it's fair to say we can start breathing easier.

The end is in sight

My heart pounded, rattling the jail bars I call my rib cage. I fought to keep my prisoner in line and continue supplying it with oxygen. The silence on the other end of the phone warped time itself as I sat on hold. I kept whispering over and over that we already had two. Finally, unable to locate my nurse, the patient coordinator returned to share the news herself:

four

We'd finally done it. For the first time, we finished an IVF cycle with an embryo loss rate from day 3 to day 6 within our clinic's standards of 40-60%. And now we have Four. Whole. Chances. Four more possibilities for euploid embryos when all's said and done in another two weeks' time. That's more pre-implantation genetic testing than I'd even budgeted for, and for once in this experience, that's an unexpected expense that I'm happy to absorb.

Decoding our journey:
- ICSI stands for intracytoplasmic sperm injection, the way our clinic fertilizes all the eggs, by individually selecting and directly injecting the best single sperm into each cell, as opposed to letting the sperm duke it out in a Petri dish.
- MII is metaphase 2, or fully mature. MI is metaphase 1, not fully mature but can potentially still mature in the lab after retrieval, and GV is germinal vesicle, a very immature egg.
- PN stands for pro-nuclei. About 16-18 hours after ICSI, you expect successfully fertilized eggs to have two: one pro-nucleus from the egg and one from the sperm. Zero pro-nuclei can either mean that fertilization failed or, if luck's on your side, that the two pro-nuclei have already fused and you're looking at a zygote: the very first cell unique to a potential future baby.
- On day 3, cleavage-stage embryos getted scored on their number of cells, their fragmentation (little portions of cells that break off during the divisions), and their cell symmetry (how evenly sized the collection of cells are). Generally, you want to see at least 6 cells. Fragmentation is scored from 1-6, but you've got a problem if you exceed 2 or 3. Symmetry is scored from 1-3, and 3 is a problem.
- Getting into blastocyst territory, Mor stands for morula, which is an indistinguishable ball of cells generally observed around day 4. EB1 is early blastocyst 1. The cavity inside the embryo is forming but it's around 25% of the ball of cells. EB2 is the next stage of early blastocyst, where that cavity has reached about 50-75% of the interior of the ball of cells.
- At last, we get to score those final survivors! The number indicates how much the embryo "expanded", with a 6 (maximum score) actually meaning that little one hatched, something I wrote about last month. I still can't get over the fact that humans hatch out of shells. The first letter is a score of the inner cell mass, what could become the baby itself. It's scored from A (many cells, excellent) to C (very few cells, poor). B is somewhere in between and is considered good.  The second letter is a score of the outer layer of cells, called the trophectoderm. Again, the scoring system is A (excellent) to C (poor).

This week has been such a rollercoaster. From a devastating fertilization report on Sunday in which it appeared a mere 7 of our original 14 eggs had fertilized to the high of Tuesday when in fact, not only had all 10 of the mature eggs from Saturday actually fertilized but, for the first time, not a single fertilized egg had failed to grow. Going into Friday, I wanted to hope but could hardly bare it after the heartache of the last two Day 6 reports.

The good news also leaves me a little salty because of how we got here: it took us three cycles to finally try (the painfully pricey) artificial oocyte activation via calcium ionophore. I know I just a dumped a word jumble on you but buckle up because a bit more's coming. As Zhang et al explain in Effect of calcium ionophore (A23187) on embryo development and its safety in PGT cycles (Frontiers in Endocrinology, 2023), 

Studies have shown that calcium oscillations are primarily initiated by sufficient amounts of phospholipase C zeta (PLCζ) released from the posterior region of the sperm acrosome. PLCζ hydrolyzes PIP2 into IP3 and DAG. IP3 then binds to receptors on the endoplasmic reticulum, causing calcium ions to flow from the calcium pool of the endoplasmic reticulum into the cytoplasm, leading to an increase in the intracellular calcium ion levels; this in turn stimulates calcium-dependent protein kinases, leading to a cascade response of cortical granule cytosolic and zona pellucida. DAG further stimulates and maintains these calcium oscillations through protein kinase C. Under normal conditions, the braking step during ICSI damages the plasma membrane of the sperm cell, leading to easier release of PLCζ, and thus, to calcium shock in the oocytes after ICSI fertilization. Nevertheless, oocyte activation fails in some patients. Some studies suggest that this may be due to the lack of PLCζ in sperm or mutations in the PLCζ gene. In addition, even sperm with normal PLCζ levels differ in their ability to activate oocytes. 

In layman's terms, if the sperm has an issue with one of its protein components, your eggs aren't waking up and they sure as heck aren't going to develop into healthy embryos. So how is there not a sperm test for this? Women are just expected to go through the pain, hassle, and emotional turmoil of several IVF cycles before shelling out thousands "just to see" if this might be the root cause of poor IVF outcomes. Do you realize how much easier it is to get a few extra sperm samples and test them for all their potential issues rather than repeatedly cycling me to figure this out?? Ugh, I can't even.

So yes, I'm thrilled that we appear to be nearing the end of our IVF journey and I am also salty AF. And tired. So tired. I can't wait to stop carefully managing a medical-appointment-riddled calendar, to get back the hours I spend each week fighting utterly incompetent health insurance reps, and to start reallocating our funds back to our depleted savings reserve rather than the endless pit of medical expenses. There's probably still a fourth cycle in the works, but probably not a fifth. The end is in sight.

The not knowing

Things started so promising yesterday morning. I awoke from my retrieval to learn we'd gotten our best haul yet: 14 eggs! We'd finally hit double digits and solidly so. Just a couple hours later, the maturation report came in: only 10 of those 14 were mature. Still double digits, but our biggest hit by far in any maturation report. And the hits kept coming: today's fertilization report dropped us down to just 7 2PN zygotes—meaning cells showing two pronuclei side by side. Technically some of those other three 0PN zygotes could still go on to embryo stage—we saw that in one of last cycle's batch, though the odds of success are lower.

I can't believe that we're just one day into this cycle's "March madness" and we've already dropped to last cycle's numbers at this point in the game despite beginning with 55% more eggs. This time around, our clinic squeezed us for every last penny with all the non-covered bells and whistles they convinced us to add on, and for what? A drained bank account and the greatest drop-offs we've seen yet. It's incredibly frustrating and disheartening.

The little bruises from this cycle's injections (52 of them) and blood draws (6) haven't even healed and I'm already juggling my calendar to squeeze in cycle number four before our big Eurotrip later this summer. (Yes, I know how lucky I am to have a health insurance that offers unlimited IVF.)

Survived: 52 injections, 6 blood draws, and 1 surgery in my own private suite. I was the only egg retrieval my clinic performed yesterday! After kicking off the weekend with a couple hours in a surgical facility, we improved things with fancy coffees, brunch, and my very first exercise of my right to vote as a French citizen. And of course no egg retrieval day is complete without some fur baby snuggles on the couch.

I know I should stay positive, but I just don't have it in me. Maybe getting down now leaves less room to fall when the next round of losses arrives. I know this is terrible framing: I'm focusing on what we didn't get when there are still seven little chances remaining. I've done this before: each cycle so far yielded one healthy embryo, yet I spent weeks aching for all the ones that didn't make it instead of celebrating those that did. Our future family may already be neatly tucked away in cryopreservation. It may be experiencing its very first cell divisions as I type these words. But I just don't know, and the not knowing is so hard.

And, in a total non sequitur, today marks exactly 10 years since Nicolas and I first met! I'd never have imagined this journey—moving to California, landing in the heart of the neurotech revolution, becoming home owners in the Bay Area, adding a puppy to the fur baby menagerie, and now exploring creating our very own lab-grown family. Life together doesn't cease to surprise.