IVF Journey: Genetic Screening of Parents and Embryos

Genetic testing of human samples

Genetic testing – (credit NIH)

[Continued from Remedies for Male Factor Infertility – Azoospermia]

The additional cost and unnatural nature of IVF has some benefits — both parents and embryos can be genetically tested in advance. If the parents have certain recessive genes, they can either use donor sperm or eggs to avoid offspring with significant defects, or roll the dice and check the resulting embryos for the issues they’d like to avoid. Most testing is motivated by a family history of genetic disease for one or both parents — it can be demonstrated that a certain inherited disease is not likely, or the opposite (in which case IVF

Our process involves both an egg donor and a separate gestational carrier (GC.) Both intended fathers and the egg donor were Counsyl tested; husband’s passed with no problems, while my genetic tests showed two fatal recessives and one “problematic” recessive (not fatal for years if ever, but weakening the adult.) Fortunately the egg donor’s test combined with ours showed no bad combinations.

The modern IVF process can freeze both sperm, eggs, and the embryos resulting from fertilization after 5-7 days; this reduces the difficulty of timing each element. Instead of rushing to inseminate fresh eggs with fresh sperm, the eggs and sperm can be frozen and thawed later for combination. The resulting embryos are typically cultured for 5-7 days and frozen as soon as they develop enough. In an echo of the quiet natural winnowing process, often only half or less of the eggs develop at all, and around a quarter look like good candidates for implantation.

The embryos are graded (letter grades!) A-D for development of the part of the cell mass that will be the child, and separately for the cells destined to form the placenta and accessories. This can be augmented by PGT-A (Preimplantation Genetic Testing for Aneuploidies) to determine which embryos are most likely to be viable. This is accomplished by taking out one or two cells from the less-critical part of the embryo and testing them. This is controversial because it is expensive, may possibly harm the embryo, and is not necessarily reliable because it’s not uncommon for cells in the embryo to have different genetic makeups (“mosaic.”) Nevertheless, choosing embryos that pass this test greatly improves the live birth rate for IVF. Desperate for offspring of their own, couples sometimes direct implantation of apparently unsound mosaic embryos, which can sometimes develop normally, but usually don’t.

Embryos that are missing entire chromosomes or major segments will either not make it to term or suffer serious defects that limit their lives. Since we are already intervening in the natural process and each attempt at pregnancy is very costly, using these tests to improve the odds is very much worth it.

While I was unable to produce viable spermatozoa, [husband’s] were fine and so we went forward with the egg donor and directed half the harvested eggs to be fertilized with his contribution.

Oct 18 2019

So they centrifuged my pathetic sample and found 4 live (if not terribly healthy) spermatozoa. Not really enough to work with!

Nov 21 2019

Egg donor at IVF doctor’ office in LA. Got an Amex charge notice, $16K, billed for the next few days until the extraction on the 23rd. 15 follicles ready, so harvest will likely be good (avg is around 10.) They will immediately fertilize half with Paul’s sample (frozen months ago) and freeze the rest of the eggs (waiting on my less-than-robust spermatozoa, which may have to be handled one-by-one.)

This first stage [husband’s] went well enough, though in hindsight we were both old enough to have benefitted from the Zymot sorting chip, which would have improved the health of the spermatozoa used for ICSI. Then we waited for reports from the culture lab to see how the little buggers did.

Nov 24 2019

Update: Got a report from the lab. Darwinian selection (which occurs silently in the normal process) underway. Of 9 oocytes, 2 rejected as immature. They thawed [husband’s] sample and selected sperm cells from a microscopic examination, then used ICSI to fertilize seven of the fresh eggs. Two of the remainder were discarded for not developing a healthy profile of pronuclei (PNs). Research has shown that the most healthy look is 2 normal-sized PNs, but other configurations (0, 1, 2.1 [one of the two is small]) have some chance of healthy development, so they are grown for more days in case they turn out fine (it turns out the male’s DNA can still be incorporated without the obvious signal of two PNs.) That leaves 5 growing. They weren’t specific about the 0N-1N-2N status of each. Kind of nerve-wracking.

Technology has improved a lot, but expect by a century from now that it will have progressed past “screening” to libraries of genetic material that can be recombined at will, and probably an artificial womb for gestation. Brave New Worldish. Costs will drop and it may eventually be seen as retrograde to have children the old-fashioned way. We’ve already seen lots of world-building where that cultural struggle is a theme.

BTW, any “super race” ideas (e..g., Star Trek’s Khan) will require a lot of arm-waving to explain how gene engineers can improve on the best/luckiest naturally born people. I don’t think (other than splicing out obviously damaging defects) anyone will be able to tailor the perfect combination of traits, and one thing we do know is that the natural diversity of talents contributes to the advantages of human teams….

Nov 28 2019

IVF update: the tech was rushed and so the report for Day 5 came in early. 3 embryos looked good enough for genetic testing (there was a differentiated clump of cells that will end up as the fetus and surrounding cells that end up as placenta, and it’s safe to remove one of those for the gene testing (shipped frozen to the lab.)) The 3 candidate embryos were then frozen. Testing comes back < 10 days. We haven’t heard from the surrogate wranglers about who might be available. I hope there’s more data to decide with. nov 30 2019 Day 7 report: the two zygotes not frozen didn’t develop and so were disposed of. 3 survivors were frozen Day 5, so that’s the choice for [husband's] kid. Kinda sad but as expected (the beyond-5-days embryos rarely develop enough). Was just reading about a PA bill that supposedly requires burial certificates for disposal of any fertilized egg. This is, of course, silly. Whether the bill actually says that is unclear, the usual amplification to get people outraged for clicks being in play. Dec 9 2019 Monday morning news: genetic tests done, 1 of the 3 embryos failed. Awww. I resent they don’t send us the report, but we can talk it over with the doctor if we schedule a Skype call. [later edit]: We got the genetic test results. Two euploid XYs (boys) and the aneuploid XY (female) who lacked the full complement of 16 chromosomes. Eek. The lottery odds favor us (only 16% chance neither XY will be carried to term) but still that worries me. [further note: I think they mean one Chromosome 16 is absent or incomplete, not 16 missing chromosomes.]

[Current state 2-1-2021: [husband’s] best embryo was implanted 7 months ago and is likely to be born to our surrogate in mid-April. We’re getting ready by buying all the equipment, clothes, diapers, etc.! We’ll get to mine later in the saga, which took much longer and had more issues with “Sperm DNA Fragmentation” (SDF) because I am older. Half of our first batch of eggs were fertilized with my sperm, and none survived culturing and screening.]

How our IVF Journey Began

I’ll try to use my personal journal to proceed in chronological order — we began knowing little about IVF, and research took some time.

I haven’t made much of it here, but my husband of 15 years is a guy, which I think, unless the PC terminology has changed recently, makes us a gay couple having children. Our new neighborhood of 60 or so houses has two other gay couples with children already in residence, so we’re not unusual. This street has many children already and more on the way since the schools are considered top-notch and we’re within easy commuting distance of San Diego’s high-tech employers.

The first reason we started to think about kids was the experience of raising two puppies. I haven’t had a pet since I was five, and the sense of taking care of and training a young animal is similar enough to raising children that I realized we would enjoy it (after the initial unpleasantness!). We had both had some desire for kids earlier in our lives, but the hurdles then seemed insurmountable and of course we were busy with work.

First entry from my personal journal, June 5, 2019:

I checked again to see if it’s too late for us to have a kid of our own. No *outright* reason not to, except the $150-200K to order up a donor egg, IVF, and surrogate mother, *and* I’d be feeble long before the child left for college. Not that upper class families shrunk from sending their kids to boarding school at 12. If you’re not independent enough by then, you soon will be. 🙂 Kid would get a nice trust fund and of course lots of attention. I can’t get anything done anyway, might as well nurture, no?

As of two years ago, we were both retired from normal full-time work, so it now seemed practical to handle the baby years. Half the stamina, but two people home most of the time!

I found some online sources, and a surrogacy agency supportive of gay couples (and run by two gay dads.) Near enough, in LA, so I talked to them and they referred us to a West LA IVF doctor to get started.

July 2 2019:

I was going to write something about our Skype meeting with the LA baby consultants coming up later, but running out of time. We’re far from designer babies, but the current crude technology and regulation does let you 1) seek out and pay a premium for the egg donor with rare characteristics (it’s a hoot that Ivy League Asian women are the gold standard for certain seekers and so get the highest payments), and 2) you can’t do gene tests of the eggs yet without damaging them, but you can test embryos by removing a few pre-placental cells early, seemingly doing no harm at that stage. By choosing those without gross abnormalities you can reduce miscarriages and select for sex. We might try for twins, actually, for that 1.5x the costs for 1 and the sibling experience….

[Husband] is onboard. Which suddenly changes our plans for later life. Sort of like a Hail Mary pass on your last down, I’m starting to downgrade my expectations for my own work to put effort into the fresh new entrants in the race. They, at least, won’t be crippled by a lack of early support.

We found out later that multi-embryo surrogacy (hoping to improve chances of having one, but often ending up with twins) is no longer considered wise; this is partly because the technology has improved so 50-60% of screened and well-timed implantations result in a healthy birth, just as high as for multi-embryo attempts which risk twins and complications. Our meticulous IVF doctor won’t do multis anymore. This became the consensus in the last five years or so. Other changes in the technology made it just as safe to freeze embryos after 5-7 days of development, which allows the implantation at the perfect time for success. So our process was 1) freeze sperm, 2) have the egg donor provide eggs, and 3) fertilize eggs with sperm via ICSI (which is now standard for late-in-life IVF — ICSI is “intracytoplasmic sperm injection,” where the lucky sperm is injected into the egg by a very fine needle.) The resulting zygotes are cultured and observed for 5-7 days, graded on an A-F scale for viability, and genetically tested to improve likelihood of a successful birth.

micorphoto of needle injecting egg with a spermatozoa]

Needle injecting a single spermatozoa into an egg.

In hindsight, the natural process for prime-aged young people is error-prone and hit-or-miss, resulting in early miscarriages and other bad things. Nature’s Way includes Nature’s Punishments. Typically the natural way is to try many times and succeed enough to keep the species going, and the winnowing process sifts out most”tries” — either the egg doesn’t get fertilized, or if fertilized doesn’t implant, or if implanted doesn’t develop properly, and is expelled via silent miscarriage before the mother is even aware of being pregnant, or develops long enough for underlying defects to cause a later miscarriage. The latter feel like tragic losses, but it’s part of the natural process and no one’s fault.

We had both done sperm tests. [Husband] did fine, I did not — my test report was stamped “azoospermia,” which means zero spermatozoa in the sample. Turns out my decade of testosterone supplementation (“exogenous testosterone”) was the cause; complex feedback loops shut down both endogenous production of T and sperm production, which made drug companies run studies of such sufferers hoping to find the male Pill. No such drugs were found, but the cause and recovery are thoroughly documented in medical journals.

So I was hoping I could catch up with time and treatment — younger men in the same boat can have fertility restored in 3-6 months, but as the doctor warned me, that doesn’t mean an old man can recover as quickly, or at all.

[Husband] went ahead and started the process by driving to LA to deposit his contribution.

Aug 8 2019:

Project stall: [Husband] drove all the way to West LA (2+ hours) to make a 10:30 AM appointment to give a sperm sample for freezing. Two hours later, he’s told “we need more than that, could you come back next week?” The legally-required FDA paperwork only lasts 7 days so you can’t wait longer or you have to pay for it again (several hundred dollars?) So he goes back Tuesday leaving here at 6 AM. At least the doc complimented him on his youthful motility.

Meanwhile, I’m just working on producing a gamete or two. Tap tap tap.

[to be continued: “How We Did It,” in installments.]

August, 2019 – Deciding to try IVF

We did a lot of research before starting the IVF process. The difficulty of adoption in the US in this era is comparable to or worse than IVF, and it’s almost as expensive, so we didn’t go that route — and besides, no one in my family is carrying on the family name, so we’d prefer to have my ancestor’s genetic threads continue.

We searched online for an egg donor. This is still an unregulated business, with some effort made to provide a code of conduct from a nonprofit organization of donation agents, but couples looking for Only The Best eggs clamor for Ivy League, Asian, accomplished concert pianist donors; which means a donor with those desirable characteristics can charge far more for her donation. Some agencies advertise “$50-100 thousand dollars for your eggs,” which is well beyond the guidelines.

We found a great donor but at one of the more mercenary agencies; she’s a graduate of a great but not Ivy League science-oriented college, she has a high IQ, and she was not that expensive as a first-time donor. “Proven” donors (after at least one successful donation) can charge more, but this was her first time. We had the agency’s help and did Skype calls to see if we liked her and vice-versa. Contracts had to be drawn up (there are lawyers for both sides at every stage of the process!) and signed.

Recognize that this isn’t easy for donors — they have to put up with medical, psychological, and genetic screening, making many visits to clinics, taking precisely-timed drugs to mature their egg follicles in abnormal numbers for a carefully-timed harvest. Our donor had to fly cross-country twice. The harvesting procedure can be painful and the wrenching-around of body chemistry can result in bad reactions. Fortunately, none of that happened and she was very successful. (And we had to have her back for a second donation when only one embryo came of the first, for reasons that I’ll describe in a later post.)

Our IVF doctor is semi-famous: “IVF doctor to the Stars,” kinda, with past clients like [redacted] and numerous Hollywood types. His office is in West LA on Wilshire, almost to the Santa Monica border, so we visited several times.

Genetic screening is a big part of the matching process. Both egg donor and sperm donor are screened for genetic abnormalities; many people harbor genes that can produce syndromes or diseases that would cause miscarriage if combined with similar genes from the other parent.

My Counsyl gene tests showed three more-or-less damaging flaws; fortunately, none of these overlapped with similar flaws in the egg donor, so we were cleared. I had two recessive conditions, plus a third which apparently is held back from the report for laypeople because it’s too diffuse a danger (sufferers live long enough to reproduce but are extra-susceptible to emphysema and liver failure.) I carry one copy of the good gene and one half-good gene (S) which means it would be wise to avoid hooking up with another carrier (and even wiser to splice it out for good, but we don’t do that yet.)…/alpha-1-antitrypsin&#8230;

Then I got my first sperm count of zero! That will be the subject of a later post — male factor infertility and remedies.

Driving to IVF clinic

Downtown LA as seen from highway

Having Children – Progress Report

I generally write on attachment theory and relationship topics to report on research results and the personal experiences of others. I try not to let my own personal experiences show too much because I’m trying for a neutral, nonjudgmental view. I have been too busy with other projects to keep up the writing and reporting here — but in a few years there will be enough new research to do another book on attachment. But for now I have more important projects!

It’s perhaps slightly embarrassing that I have weighed in on child-rearing topics but never had children until now. So we’re almost too old to undertake such a project, but we have the time and the space for it now.

The first few minutes of Idiocracy humorously cover the modern issue of long-delayed (and often foregone) children amongst the highly-educated, well-off young people of today, who may well stay in academia and avoid commitment until they are in their 30s and 40s, thinking “we must have stable jobs and resources before we have a child.” This is biologically risky since women’s eggs begin to slowly decline in quality after 25, and drastically after 40. Males, too, decline in sperm quality with age, though not as quickly (since sperm are generated from stem cells on demand, rather than being stored as buds from birth as eggs are.) Couples who want to have children but find their fertility has waned sometimes use IVF. A would-be mother whose eggs are too dicey can use a donated egg, and if unable to carry, a gestational carrier (the modern term for surrogate.) Anonymous male sperm donations are (compared to eggs) relatively cheap if it’s the male who has the issue with fertility. IVF procedures have improved greatly in this decade, and it’s a good thing because women are tending to postpone children for careers and men’s sperm is rapidly declining in potency. In a few generations perhaps most children will be IVF babies — presuming the price declines from the current $40-100K per child.

So I’m going to write more about these much more personal topics. We have (as mentioned elsewhere) embarked on our first child; we started in August of 2019, and our first is due in April of 2021 (21 months after our decision, delayed by COVID-19 shutdowns and other snags.) We found a great egg donor and have a second (and perhaps third) frozen embryo ready to start this month. The embryos have been screened and graded, and PGT-A genetic tests (not completely reliable) say they are all healthy boys.

20 Week Ultrasound

Ultrasound at 20 weeks

We moved from a comfortable home on a golf course in the Palm Springs area because public schools weren’t very good there, and since there were no children in miles (the average age of our neighbors being 70), we moved to Carmel Valley in San Diego, which has fantastic schools and a neighborhood that will have hundreds of children within walking distance. We want them to grow up like we did, free to roam the suburban area by bike and walking, to build peer relationships with a wide variety of other children.

I’m planning to post the history of our IVF experience before the first baby arrives. The initial 6 months of caring for an infant are pretty much all-absorbing, so I won’t have time to post much until after that.