A few more in the freezer

The latest round of embryonic March madness is drawing to a close, and another 3 fighters made it to be biopsied and cryopreserved. Now it's just another 10-14 days until we get the pre-implantation genetic testing results to know what we've truly banked. In a first for us, one of our poorly scored day 3 embryos actually made it into the final countdown. (Embryos get rated on day 3 based on number of cells, fragmentation—the fraction of the embryo composed of incomplete cell chunks, and symmetry of the cells.) This embryo proved to be our ugly duckling, coming through as the most highly scored embryo on cryopreservation day. Proud of you!

We did it—again!

Another cycle in the books. Now to let the embryos grow (hopefully)!

This cycle was our best so far—a full 25 follicles at my final monitoring appointment, no ovarian or breast pain, and frankly I walked in and out of today's retrieval feeling great. I didn't tear up even a little when getting my IV. In fact, I kept my eyes open during my last blood draw earlier this week, and even snuck a peek at the blood mid-flow late last week—talk about overcoming a phobia. To top things off, I had surprisingly productive afternoon in the office after the ritual post-retrieval coffee cocktail at The Royal in downtown Oakland.

That's not to say we got a drama-free cycle. There was an FDA test scare that required a last-minute re-run of the full panel (after much cajoling), and due to an inconveniently week-late ovulation, my retrieval timeline was pushed precisely to the day after Nicolas flew out to Europe. My battles with Cigna continue—although they now, for the most part, acknowledge that Nicolas isn't my sperm donor, I found myself yesterday filing my first complaint with the California Department of Insurance under Spring's guidance.

After all the highs and lows, here I am enjoying an injection-free evening while the fate of another 10 mature eggs lie in the hands of Spring's embryologists.

Even Lily got in on celebrating the end of my fourth cycle!

And guess what else? My parents send us their congratulations! That's right, now that we're done* making our embryos and our future surrogacy agency has acknowledged receipt of our retainer fee—yes, that also happened today—it was time to share the news, which went over pleasantly well. They even said I shouldn't feel guilty about the choice to use a gestational carrier. It'll be a secret from the rest of the Aloia/Repak clan for now—no need to jinx it or break the hearts of cousins whose dream we might be trying on for size—but getting my parents' approval about becoming a parent on my terms has lifted a weight that was bearing down heavy for the past 8 months. It's nice to have earned a night off.

*done: as in, we think we won't be making more, but life is complicated so I still took my vitamins tonight just in case.

Second "vacation" of 2024

Indisputably our second stab at taking time off this year was more successful than the first. I hardly answered any slack messages and didn't even write a line of code. That said, attempting a vacation between back-to-back IVF cycles was probably overly ambitious. To our credit, when we converted our Amtrak credits into our first trip to Colorado, we never imagined what our fertility journey had in store.

We landed back home a full week ago and I honestly don't have the energy to do much more than tell a story in pictures. We did a lot. I worried a lot. And I didn't fully absorb the good news that arrived a week ago today as we sat in the airport, en route home, and learned that we had reached our minimum threshold for making our future family.

Here's the best I can give right now at telling the story of a few days where we had a change of pace.

Things started off scenic with our overnight train to Colorado. I can't recommend highly enough the upgrade to the sleeper car that we thankfully splurged for. However, my anxiety levels weren't aided when, before even making it to our destination, I found myself texting photos of Lily for "lost dog" posters after she ran away. One four-lane highway crossing and several hours later, a kind stranger returned her to our dogsitter and I tried to remember to breathe.

We made it to Glenwood Springs and our first taste of summer weather! The town kicked off its 127th annual Strawberry Days Festival right when we arrived.

We were up early the next morning for the first activity on our agenda: paragliding! Sadly, I learned that my stomach is just a wimp. Even with a fabulous pilot who took seriously my ask that we have a smooth ride, the rises and dips just left me feeling a little queasy for an hour or so after the ride. Nicolas, I'm proud to report, isn't nearly such a weakling.

Item 2 on the agenda was actually both the scariest and the coolest: the caving "wild tour". They weren't kidding when they said there was a chest size limit of 42". We shimmied and squirmed our way through passages whose mere discovery amazed me, while I thanked the stars that Colorado isn't on a fault line and admired the heck out of the mom on our tour taking her 11-year-old adventuring for his birthday.

After proving to myself that I could be brave both above and underground, we took the gondola back down and spent the evening in some (overcrowded) hot springs. The pools were all designed to mimic mineral compositions of various springs around the world and, what do you know, I settled on Iceland's Blue Lagoon (which we've previously visited) as my top pick!

Nicolas, who's prepping for his big hike in the Alps in a month, convinced me to brave the heat and we even got some nice shots as we explored Boulder. I'm not sure just when I became a total princess, but it seems I've built a taste for the tastier parts of vacations.

Between hikes, we rewarded ourselves with lunch at the most fabulous university dive bar. It completely tickled my fancy with its MIT East Campus/Senior House vibes and had a great beer selection too!

We dodged the rain post afternoon-hike at Boulder's teahouse, created to celebrate its sister city status with a city on the other side of the Iron Curtain.

And just like that, it was basta - enough. We'd spent two and a half of our five vacation days in transit, so perhaps this wasn't the most well-planned trip, but we'd squeezed in a lot. We capped it off with a trip to Basta, a Michelin bib gourmand rated restaurant where I ate probably twice as much pizza as I'd needed. And that was it. Vacation numero dos was in the books.

The first calls

We had our first calls with surrogacy agencies today. I felt so seen, so heard, so respected in my choices. There wasn't the slightest wince as I told our story, from our meeting through online dating with profiles that listed our intent to be parents as "maybe" to our journey into foster parenting to our round-about arrival at IVF and surrogacy. My wanting to care for and love a child could co-exist with my not wanting to grow it inside of me (and a recognition that the stress and sleep deprivation of my job might not be best for either mom or growing baby). I wasn't judged or made to feel less valid than those seeking surrogacy out of medical necessity. Not only that, I was met with positive reactions as I counted off our four euploid embryos and our one low-level segmental mosaic. The reps praised our choice of fertility clinic, whose embryology lab has particularly high standards, and they taught us that, when working with a surrogate, odds of a live birth from a genetically-tested embryo climb to 70-75%. Now that the healthy and genetically-tested embryos have been banked, my age is no longer a risk factor. For the first time since we began this scary and unexpected journey, I'm wracked with sleeplessness over something new: excitement; hope.

I don't want to sound overly naïve: I understand that surrogacy agencies are a business, and that they have a financial interest in making me feel good, but two things can be true at the same time. Just because one of these agencies may make a profit off of me doesn't mean they can't also bring me validation and the fulfilment that proved so elusive as we fought tooth and nail to make last year's foster placement work. 

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.