Welcome to Fertility and Sterility Unplugged, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussions with authors and other special features. Fertility and Sterility Unplugged is brought to you by the Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine and is hosted by Dr. Blake Evans, Dr. Daylon James, and Dr. Molly Kornfield.
Hello everyone and welcome to another episode of FNS Unplugged. I am your host and recently appointed FNS Interactive Associate in Chief, filling in some big shoes that Pietro had left me. Blake Evans is my name.
You guys know me if you listen to this podcast. We're just kind of doing some role shuffling, if you will. So Pietro unfortunately won't be on this podcast, but he will still be on the FNS On Air, as he usually is.
So I'm with my lovely co-host as always, Dr. Molly Kornfield and Dr. Daylon James. How are y'all doing? Terrific. A little sad, but also quite happy.
I'll miss Pietro only a little bit. And while those are big shoes to fill, you're very tall, Blake, from what I know. So I think you're right there.
Thank you so much for that. Molly, how are you doing? I'm doing good. Sorry for the vacuuming in the background.
I'll go last today, but this is real life. It's real life. Vacuuming at home while you're recording a podcast.
Yeah, that's okay. We're going to roll with it. Well, I'm going to kick us off.
I'm still going to do an FNS Reviews article, although we're still working on having a newly appointed media editor for FNS Reviews. So to be determined on that, but I'm going to do a Reviews article today. So the title of this one is Obstructed Hemivagina and Ipsilateral Renal Anomaly, also known as Ovira Syndrome, Developmental Pathways, Candidate Genes, and Clinical Implications.
This is by Driver et al. I'm out of Howard University and senior author and friend of mine, and also a fellow Oklahoman. Most people don't know that about her, Dr. Kamaria Clayton Vaught out of Hopkins REI program.
So Ovira Syndrome is, have you guys ever seen this before? Ever heard about it? It's quite rare. I have. We probably get a few a year.
Yeah. It is overall quite rare. We do see it in our neck of the woods though, because these patients are often presenting in the adolescent population for primary amenorrhea or pain with menses, for example.
And so oftentimes these are even with our PAGS colleagues, at least at my institution it is. So first I'm going to talk about what is it, why it happens and what we still don't know about it. So Ovira Syndrome, also called Herlin-Werner-Wunderlich Syndrome, as it so eloquently rolls off the tongue, is a rare congenital condition that affects women.
As I mentioned, typically discovered in the adolescent population. It involves three main features. So double uterus or uterus didelphys, and then one side of the vagina is blocked.
So hence the obstructed hemivagina. And the kidney that's on that side is also missing. So ipsilateral renal agenesis.
And most girls don't show symptoms until after they start having menses. There's a blockage on this side, menstrual flow backs up and can lead to a lot of pain, even endometriosis. And discharge at times, vaginal discharge and a pelvic mass as well.
So if left untreated, endometriosis, as I mentioned, can progress. Blocked fallopian tube on that side and very, very rarely a cancer even. So how do we diagnose this? Well, so of course having suspicion for it is one thing, but MRI is the gold standard of confirming Ovira syndrome.
Left side, interestingly, is more commonly affected, but up to 50% of cases involve the right kidney or even the opposite side. Just keeping the mind guessing. So again, what causes Ovira? We don't know exactly what causes it.
Traditionally, we thought this was a problem with how the malarian ducts fuse. So for those keeping score, fallopian tubes, uterus, upper third of the vagina or the malarian ducts. But it also involves the kidney, which as we know is from a different area of the embryonic structure than the mesonephric ducts.
And so this mismatch suggests that something deeper may be going on in development. There are models that suggest that the Wolfian duct may play a role, so which forms the male embryonic structures. And this guiding both the systems, the malarian structures, and mesonephric ducts to the correct spot.
And so perhaps an anomaly in the Wolfian ducts leads to Ovira syndrome. There are possible genetic causes. There's no single gene that causes Ovira, but evidence does point to a possible multifactorial model.
So possibly genetic, epigenetic, or even environmental factors have been proposed. There some candidate genes that have been found. Again, we can't point the finger at any one of these, but there have been some common denominators that possibly point to causes.
So WNT4, shout out to all of those who took REI written board yesterday. I'm sure you had a question or two on this, but this is a gene that's critical for female development and kidney formation, and one of the first signaling molecules identified in the ovarian determination pathway. Some other genes that are lesser known, or at least to me, I hadn't heard of these CHD1L and RET, this involves ureter and kidney development.
And a few others that, so TGF genes found in one patient in addition to TRIM gene. These are, again, genes I've never even heard of these genes, but possible digenetic or a two-gene inheritance. I like this one, GREB1L, because it kind of looks like gerbil.
I haven't heard of that one either, but that's my favorite. Yeah. But I do like, yeah, anything that looks like an actual word, I appreciate that more.
So the gerbil gene, you don't want to have the gerbil gene. And so I was kind of proud of myself for this next one. I saw 22Q11, and I thought way back in my mind to pathology days in medical school and DeGeorge syndrome.
So that's DeGeorge syndrome. And I even looked it up and I said, isn't this DeGeorge? And Chad GPT said, yes, it is. Good job, Dr. Evans.
And so there's some associations with DeGeorge syndrome and having a viral. Some other genetic or copy number of variants, 16P11, 15Q11. There are some familial cases that exist, including siblings and even monozygotic twins, interestingly, therefore implying a genetic ideology.
But some have even these twins have opposite side involvement. And there's also been incomplete penetrance. So a sibling has it or a father has it.
Their sibling does not have it, but then their kids have it, for example. Or their, excuse me, their child has it, but then their grandchild does not have it or may have it. So a viral doesn't always happen alone.
There have been cases in which 271 patients across 17 studies looked at have skeletal issues like scoliosis, also have heart, vascular, digestive problems. This supports the idea that it may be even part of a broader mesodermal developmental disorder, not just localized into the reproductive tract. So it also overlaps with genetically related conditions like malarian agenesis or Zinner syndrome, which I had to look up is basically the male counterpart of Ovira, where you have unilateral renal agenesis, ipsilateral seminal vesicle cyst, and ipsilateral ejaculatory duct obstruction.
I've never heard of that. Have you? Yeah. And our studies for RAI boards, I'd never come across that.
So genetic testing, although can be done, it is not without flaws, can be difficult to localize specific genetic disorders. So chromosomal microarray usually detects big deletions and can miss the small or the non-recurrent deletions. Whole exome sequencing finds coding variants, but has somewhat of a low diagnostic yield, according to the authors.
And then some of the issues may be just tissue specific. So it's not in the blood, could be epigenetic and therefore requiring a deeper analysis. So the authors propose, as we're kind of wrapping up next steps with this subject, authors propose to start with CMA, chromosomal microarray, and do a whole exome sequencing thereafter, consider tissue specific genetic testing, and then of course these studies have to be validated moving forward.
So what do we need to know moving forward as providers? Because this can be treatable, surgery to remove the blockage, the hemivagina, that is obviously going to be one of the most important things to relieve pain and prevent endometriosis development in these women and early diagnosis is crucial. And so, as you can imagine, this is going to involve a multidisciplinary team, gynecology or REI, urology, nephrology, even genetics possibly. Comprehensive imaging, MRI imaging is recommended, get a detailed family history, referral to a geneticist for further evaluation as well.
And so, also the authors say that standardized phenotyping would be helpful, or even having like a global registry for these patients, even studying male counterparts. So if we find males with the Zinner syndrome, like I mentioned, are there possible shared genetic pathways? So that would certainly be interesting there. And so, until we've pinned down the exact molecular cause of this, it is going to remain a puzzle, but one that's becoming a little bit more clear as these new genetic tests and family cases are discovered.
So, nice little summary from our friends at Hopkins of a rare condition, but certainly one that we see and we should be on the lookout for to get these patients treated early and relieve pain. So what do you guys think? Any thoughts about this? I have some thoughts, which is from the developmental perspective, the takeaway for me is just how many things need to go right for not just a human or any animal embryo to take form and survive and go on, give rise to progeny. You need a lot of things to go right.
And there's so many things that can go wrong that converge on the same phenotype. So I really appreciate the challenge that this group met in providing as comprehensive a synthesis as you can with something like this, because there really is no molecular cause. There are multiple hits that in different backgrounds can have a range of effects at different time points during the formation and sculpting of the female reproductive tract and the male, of course, as well, as you're alluding to there, Blake.
So for me, the takeaway is like, I don't know that we're ever going to be able to zero in on a single cause, but we will, I think, be able to understand and predict all the variant causes and likelihoods that single mutations or polygenic variants in genes may converge on a phenotype that resembles this ovira. Because, you know, the author said that the genetic sequencing, exome sequencing, may be a limited resolution, but that's a moving target. As the databases get broader, as the sequencing gets cheaper, and as we're approaching now, I think, a sequence all paradigm, I think we're going to understand all the variants that can lead to ovira and we can predict which patients at birth are already affected, really, because the reproductive tract has already formed for the most part, and maybe come up with some treatments.
And I guess that's my, where I'm going with this, is like, if you could diagnose this right off the bat, is there something you would do differently with those patients during their adolescence at whatever point? Or is that like early surgery for repair? What would be your strategy if you could get right out of the box, ovira diagnosis and intervene? I would think when these children present and they're having like really severe cyclic pain and, you know, often they're turned away, people say, oh, it's probably endometriosis or dysmenorrhea at first, because you're not going to think malarian variant when they're cycling every month, when they're bleeding every month. And so these ovira cases are often missed for a little while. And by the time they're in the hospital and they're calling us to see them and they're catching it finally on a CT scan or ultrasound, they're in a lot of pain.
And so I think if you could foresee this, I don't know how, you know, some vaginal surgeons may want them to cycle a few times before they would do the case. Sometimes it's easier when things are a little more distended. But I think that you're right, Dale, on having this information early on.
And some of it may be, you know, our prenatal ultrasound's gotten so much better. So I don't think we may not catch a hemivagina, but we would at least catch a didelphys and have some suspicion there. So early counseling could prevent that suffering for the children.
Yeah, absolutely. And then, you know, if there is a specific gene involved, and particularly one that's associated with heart or vascular disorders, I mean, obviously, that would be extremely important to figure out earlier in life and then get them to see a cardiologist or a GI physician or, you know, orthopedist, you know, something like that. So it may not just be purely a malarian issue, and they could have some more really serious medical issues to really consider and address.
Yeah, that is a good point. They got bigger fish to fry probably in many cases. And that is, again, because some of these genes, it's two parts of that.
Some of these genes, they do so many different things at different points and in different tissues. And in some cases, there's enough redundancy. I would imagine that, you know, the single gene defect isn't necessarily going to lead to the manifestations of OVIR.
But, you know, as our understanding of that polygenic contribution becomes more sophisticated and nuanced, I really think that we're approaching a new world of prediction and diagnosis. And I'm not excited about it, to be honest. I think it's going to be a really scary time, fraught with anxiety and false positives probably in a lot of cases.
So who knows what that world's going to look like, but the capability is near there. So you're saying ignorance is bliss? In my case, yes. Well, kudos to the authors.
Great publication. So we're going to shift gears, and Daylon's going to talk to us about time lapse and morphokinetics and some zygotes. Yes, we talk about prediction and we talk about ignorance is bliss.
I mean, here's a question for you guys, you know, these 3PM embryos. I think it was nice and tidy. 3PM, that's not right.
We're not transferring that. Was kind of the case with mosaicism. Now that's maybe up for debate.
Is there a cross-the-board position that your clinics have on 3PM? Or do you get a lot of 3PMs? We don't get a lot of 3PM, but if we did, then we would not be transferring them at our facility. How about you, Molly? You ever see any 3PMs? For our current protocol for 3PMs, and sometimes these things are a moving target, I think we would not be transferring or continuing to culture these. 0PNs, 1PNs, our practice has definitely changed, but I believe currently we're still not transferring glossocysts from 3PMs.
Yes, and that's the beautiful and, I mean, frustrating thing, and sometimes with our field, it's provisional, all of the standards, SOPs, and nowadays, you know, while 3PN, these triploid, assumed to be triploid, in most cases, 3PN embryos have typically been excluded from embryo transfer. There's mounting evidence that not all of these 3PN embryos are actually chromosomally abnormal, right? In fact, there's a phenotype called 2.1PN, or micro-3PN, that's been identified as a subset of these 3PN zygotes that has been reported to be diploid and capable of developing diviable blastocysts, even live births resulting from those. So there's a few reports, a couple of live births, multiple of blastocyst formation, and those zygotes that are quote-unquote healthy here are typically characterized by the presence of two normal-sized pronuclei, and then this third, as the term micro-OPN alludes to, this third visibly smaller pronucleus, and that delta in size has been attributed to chromosomal lagging or aberrant partitioning of maternal chromosomes.
But in a previous commentary, in actually a consider this, so look at that, consider this article that groans up. This was a couple of years ago in Fertility Sterility, and now the authors have built upon that case, and in that considers, they argued that some 3PN zygotes may be diploid from the start. It's not like a repair, but they're diploid from the start, and they just have this abnormal but not necessarily pathological phenotype, and they proposed this novel nomenclature of a partitioned female pronucleus to describe the cases where there's this incomplete maternal chromosome segregation, and therefore this additional micro-pronucleus, that while there is a micro-pronucleus there in aggregate, you have overall diploid chromosomal complement.
I have to be honest, looking back at the consider this, I was a little bit skeptical that you could like chop up and then, you know, have a different number where all in aggregate, you'd still have the same number of chromosomes. I was a bit skeptical of that, but you know, knowing that a couple years later, this group, which was led by Masahide Shiotani, who's at Hanabusa Women's Clinic in Hyogo, Japan, and the group there wanted to develop this non-invasive time-lapse imaging-based approach to stratify these 3PN zygotes, because they had come out with this consider this article that there was a subset of these so-called triploid, but actually diploid 3PN or micro-PN zygotes, right? So they were able to aggregate an impressive number. Part of the reason I asked you guys, because I think it's incredibly rare.
I don't think you guys are in the minority. If I asked a lot of REIs what their experience with 3PN, they'd be scarce. Here they, based on a total 222 3PN zygotes, including 173 that were classified as actually diploid, and 49 that were classified as actually triploid.
They looked at the ratio of the combined female to male pronuclear volume, all right? That was their metric, and that metric was correlated with some values, with the idea of it being predictive of the overall health, because they wanted a proxy measure. How could they identify the actual diploid without having this destructive measurements? So they did time-lapse, and this is another integration of, I think, modern tech that's really exciting and powerful, is all the morphometrics and, of course, the AI. I'm not going to go deep on that, but here I think a really straightforward use of morphometrics, which is just to define which of these actually had that second polar body extrusion.
So they could go back in time in the time lapse and see which of those had polar body exclusion versus those who had a failed extrusion, and they separated those two, showed that overall blastocyst formation was a little bit better, 40 percent in that positive extrusion versus 32 percent in the failed extrusion group. Here it was the real, you know, juice after the squeeze, and that was good quality blastocysts. It was 23 percent in the extruded group, whereas less than half of that, at 10 percent in the extrusion failed group, and then adjusting for maternal age, they concluded that while the presence and proof of polar body extrusion did not significantly associate with overall blastocyst formation, it was associated with higher odds of good quality blastocyst formation.
And here was kind of the kicker, although I don't think very scientifically controlled, because you really can't do that, they actually had a subset of these embryos that were transferred under very specific policies that were unique to each site, so it's hard to really draw comparisons, but they showed seven live births from these embryos. So I think like very clearly now, embryos that may be phenotypically triploid or, you know, these micro 2pn are clearly capable of giving rise to live birth. I don't know if I would, you know, bet the farm in terms of the predictive value of this ratio, the female to male pronuclear volume, because the differences weren't that huge, but they were real here.
And I think that's the takeaway that we're moving towards, and we have the framework in place, and this volume ratio combined with other morphometric measures, maybe even some that us humans don't understand, just let the AI run wild, may be able to come up with some real value in these specific cases where there aren't a lot of choices, and extending that beyond, of course, in just garden variety cases of maybe mosaicism, or even beyond just embryo quality, which is the holy grail in terms of using morphometrics for a solid predictive algorithm. But this to me seems like a real morphometric equals predictive value light, and I think we're moving towards something that's going to be more robust and exciting and practical, I think, for you guys in the clinic, if you ever do run across a triploid embryo. What do you guys think? Would you use it? Would you use the algorithm now, or are you just safe for saying, you know what, let's just keep those on ice? We'll do another cycle.
I may have missed this, but do they do genetic testing on these? Do they do PGT? Let me look into the metrics. I think they would have. I'd be surprised if they didn't, but in that it was an observational study, and across multiple centers, I could also see that there wasn't any standard approach that they could integrate.
So, I don't know. I'll have to get back to you on that, Blake. Yeah, that was just my main thought is, you know, we have this fear of actual, you know, biologically plausible fear.
Like, it's very reasonable to understand why we would not want to transfer these 3PNs, but if you were to then do testing and do PGT, of course, that's not end-all be-all, not 100%, but it would make you, me personally, feel a lot better about transferring a 3PN embryo, but I don't know that I personally would go based off of just the time lapse, but it is, you know, reassuring. Of course, having more embryos available for patients to transfer, I think that as more and more testing comes out, it's going to be, it seems like counseling for these embryos, whether it be 3PN or segmental or high-level mosaic or low-level mosaic, counseling just becomes harder and harder and harder, and we're not going to have enough time in the day to counsel more than one patient about their embryo. So, we need to have a genetic counselor on standby at all times to talk about all these things.
So, that's my thought. Too much information, yeah, and I'm looking here, I don't see any information about PGT, and yeah, I think that revising, I think that when you see 3PN, you're not working with that embryo at all. You might, for academic value, track it in the embryoscope, but I don't think anybody's really going to waste the, not waste, spend the time or money on that biopsy.
But I think that would really prove their point, yeah. If we could, you know, obviously, there's limitations of trifecta during biopsy. We'll go on to that with the next article, but I think that would reassure me for a patient who really doesn't have other options, had two frozen eggs before chemotherapy, and that's all we've got is this 3PN.
Then with appropriate counseling, if this kind of pans out, looking at the morphology of the nuclei plus PGTA with testing for uniparental diastemia with counseling them about the molar pregnancy risk, then yes, that would be reasonable, I think, to proceed. Absolutely, and now I think the rationale is there. I don't think anyone would have thought to do a biopsy on it, but now, at least academically, I think they're going to lean in on this, and that's what you can hope from, the best you can hope, I think, from an FNS, you know, science article that's on the cusp of clinical translation, is that someone takes the ball and runs with it, and I, in my own clinic, I'm certainly going to advise embryology to, you know, save these embryos and use them for experimental diagnostics and research.
So, another arrow in the quiver, so to speak, not saying we're safe for prime time, but definitely something worth looking deeper into. Yeah, and a nice little narrative on how Consider This article helped inspire an FNS science manuscript. So, well, thanks, Daylon.
Nice little segue to Molly's discussion about the limits of genetic screening. So, go ahead and fill us in on what you got, Molly. Great.
So, this article, it's another case report. We've had just this run of really interesting case reports and FNS reports lately. So, this one is The Limits of Genetic Screening, Trisomy 21 After Euploid PGTA and Negative NIPT, first author Jennifer Law and last author Joanna Perdigao at Loyola University in Chicago.
So, this case report is a patient who transferred a euploid embryo following IVF for a history of tubal ligation. She's 40 years old, and she delivered a child who actually had trisomy 21. So, this patient had a prior tubal, desired additional fertility, underwent IVF, and she was 40, was probably counseled on the benefits of PGTA, so did undergo PGTA, and had a day 5 blastocyst that had been genetically tested to be euploid 46XY transferred.
The platform that they used was M-GenX PGTA kit on the Illumina NextSeq NGS platform. And by that platform, they said that the estimated mosaicism of less than 30% is reported as euploid. And so, I think we're all fairly familiar in our field with that our different genetic testing companies might have different thresholds at which they'll call an embryo euploid, low-mosaic, high-mosaic, aneuploid, as well as some labs just say euploid or aneuploid.
They don't even have a range of mosaicism. And so, there's a lot of variation there between labs. And even within one testing company, different IVF centers can choose different thresholds as well.
So, this particular lab reports mosaicism of less than 30% as euploid. For IVF cycles, she had three additional embryos that were retrieved and biopsied. One was euploid and two were aneuploid.
But of note, neither of them were reported as trisomy 21 as they're aneuploidy, which I think is a natural question of, oh, was the embryos flipped or something like that? And then her pregnancy continued appropriately through the first trimester. And at 10 weeks, she actually had an NIPT that returned low risk and had a 10% fetal fraction. So, that's considered a sufficient fetal fraction to have a pretty reliable diagnosis on your NIPT.
And it was low risk for trisomy 21. She had a reassuring anatomy ultrasound, but then she did develop polyhydramnios in the third trimester and had a double bubble sign that was concerning for duodenal atresia, which is one of the markers for trisomy 21. She was offered an amniocentesis, although many patients won't be accepting that in the third trimester, but I know many MFMs do offer it, and declined at that time and then ended up with severe polyhydramnios and delivered via an induction in the 37th week.
At birth, the child had facial features that were consistent with trisomy 21 or Down syndrome, and a chromosomal analysis of the infant's peripheral blood with an extended cell count out to 50 cells confirmed this was a sporadic Down syndrome with no mosaicism detected. And I think that part is really interesting that mosaicism was detected. The PGTA lab was actually contacted and they asked, hey, is it possible there was some mosaicism for T21 that was under that 30% threshold? And they said that they'd actually don't report or disclose findings below that validated reporting threshold of 30% as it's not clinically appropriate to do so per their lab's kind of policy.
So the authors kind of go through and review that PGTA and NIPT are highly accurate, and they do have good negative predictive values. And so negative predictive value for PGTA, we usually quote 94 to 100%. I've seen 100%.
Clearly, that's not true based on the study. And then the NIPT sensitivity and specificity tend to exceed 98.8%. But this is a case where the trisomy 21 was present despite a low-risk PGTA and a low-risk NIPT. So to have both tests not be accurate is certainly interesting.
The authors write that from their sense, they believe this was a case of mosaicism in which the mosaicism was not detected on the PGTA or the NIPT. And so that it could have been sort of aneuploidy within the inner cell mass, whereas the trifectoderm was mostly euploid. And then the NIPT is actually derived mostly from placental tissue.
So if you had a mostly euploid placenta, that wouldn't show up on your NIPT. Another possibility since the PGTA did not kind of release with that less than 30% was if there was a mosaicism there, a very low-level mosaicism, this could have been error. This could have been a lab error.
This could have been that the wrong biopsy was sent. It's certainly possible. We think of these as never events in our labs, but we know that it does happen.
And I think I'd be more concerned if they said, hey, her aneuploid embryo was trisomy 21. Then I'd say, I think these just got switched in their straws in terms of what they thought or something. But the other piece is, you know, if I read this case and they said, yeah, it was a natural cycle embryo transfer, I'd go, well, we know this is almost impossible.
I think she just got pregnant the same cycle, but she's had a tubal ligation, which makes it a really kind of perfect case report to pinpoint the issue here. And I have to think that this false negative rate is going to be higher in AMA population, just based on kind of the population rates of aneuploidy. I think patients often ask me, hey, I did PGTA, should I still get the NIPT? And I'm like, well, our MFMs and our OBGYNs are pretty much still advising it and offering it.
And should I get the amnio? Oh, well, that's potentially more detailed with microarray and everything. But generally, NIPT for someone who's done PGTA with transfer to euploid embryo has a positive predictive value of 7.7%. So you do end up with a whole lot of false positives for these patients, which can be very stressful. It means they might have to go undergo an amnio at that point.
And the 7.7% of positive predictor value is one case where the NIPT was chromosomally abnormal of a PGTA-tested embryo, and then ended up being a chromosomally abnormal pregnancy. NIPT is also really not well-designed to detect mosaicism, the authors highlight. So if the chromosomally abnormal line is really underrepresented in the placenta relative to the fetus, it might not be picked up.
And then as we talked about, NIPT is placental DNA. So usually we think of sort of this inner cell mass that's euploid, and then this mosaicism of the trophectoderm. And this is kind of the opposite of how we would think, but we know trisomy 21 is compatible with life, so it seems possible.
And then lastly, the authors propose there's going to be a mitotic error in the fetus as well, or this initially trisomic embryo that then had trisomy rescue in the placental cells. So sort of that same or similar concept. But overall, I think there still is a role for amniocentesis in obstetrics and MFM.
I mean, most MFMs and obstetricians wouldn't argue about that. But even for your patients who've done PGTA and have a low-risk NIPT, I think it's still worthwhile to offer an amniocentesis and make sure that they're really well-informed. And this case report certainly changes my counseling.
I don't know what you guys think about it. Yeah, that's kind of scary. You know that GIF of Zach Galifianakis when he's in the casino, I think it was the movie Hangover, and he's like looking and he's thinking, and there's all these mathematic equations swirling around his head.
That was, I feel like, me this whole time you were talking of like, how did this happen? That is so unfortunate to have not only a normal PGT test, but also the NIPT and then still end up with this. But yeah, if anything, I mean, we never say 100% in our field, right? Like I'll jokingly but also seriously say to my patients, I never say the word promise or a guarantee or this will happen or, you know, because you'll get those times where the nurses are like, hey, this patient said that Dr. Evans promised that this would happen. I'm like, no, I literally never say the word promise.
So similarly with PGT testing, I think it's crucial we never say 100% because of very rare things like this that can occur. But case reports like this just remind you to, you know, we need to be very cautious when we counsel and our consents have to be just so clear that this is not a perfect thing. But man, still to have the normal NIPT in addition to the PGT testing, that's just very unfortunate.
To still go into pregnancy, you think everything's just fine, and then you still have these issues come about. But scary, very unusual, but definitely a good reminder that these tests aren't perfect that we offer. It makes sense because it's the same error twice, right? The 200th cell with the trophectoderm and then the placenta, but it kind of makes sense.
I'm also surprised the child is not mosaic. I thought that really surprised me, especially because they did 50 cells on their carrier. I'm so surprised to find that.
So just to clarify, you're saying you would recommend that every patient undergoing IVF, or if there's a reason to do PGT, then you should do NIPT and amnio? Not amnio, but it is just recommended. I'm saying Molly ended with kind of a cautionary note. I just wonder if that, I mean, because I'm probably over-denominatoring that.
It's not everybody who's in the clinic for ART, right? We're talking about a subset of high risk. Are we saying anyone who's doing PGT and then, of course, NIPT? Yeah, right. So even if someone had a PGT-tested embryo, the recommendation is still to offer and recommend they undergo first trimester screening.
But despite that recommendation, and this patient did both of them, it still came back to normal. Did she do amnio, this patient? No. I guess that's what I'm asking, because there is a clear risk with amnio.
So I feel like there's a number needed to treat idea here, where is this truly a fluke? It sounds like a fluke to me. It almost doesn't justify... I'm asking because I have zero judgment period, much less clinical judgment. So what is the... Maybe a little bit of judgment, but not a lot.
Would you really revise your practice to now be like, you may want to... I'm offering you amnio. Amnio to all. I think everyone should get offered an amnio, right? And amnio has higher resolution than NIPT as well.
Most NIPT is just checking trisomy 13, 18, 21, sex chromosomes. Offer it or recommend it? Offer. I would offer.
I don't know that people would recommend, but I think you have to know your patient and what is it that they fear most? What is it that they hope for the most? What is their prior experiences? What are their prior experiences? So this is about managing... You don't want... It's a patient-specific thing. I think anxiety is peace of mind. Not necessarily about the risk.
It's about not like the objective risk and number needed to treat. This is about letting your patient have full agency. Yeah.
I don't think it's cost-effective for all these patients to undergo an amniocentesis. I bet you could make a good case that NIPT isn't even cost-effective with a positive predictor value of 7.7% for PGTA-tested embryos. But I think if a patient says, oh, I have a child with T21 who had really serious cardiac anomaly related to it or leukemia, right? We all know people with T21 who have wonderful full lives, but we know there's really significant medical risks for these people.
And they said, the most important thing is that I do not have another pregnancy with T21. Then I think an amniocentesis for that patient makes sense. But I do think the number needed to treat, it's got to be 1 in 10,000 or something.
Yeah. It's got to be quite high. For the total test to fail.
Yeah. Yeah. Yeah.
That's unusual. Well, very interesting. Well, thanks, Molly.
And thank you all for enlightening me on these enriching discussions. As always, it's great to chat with you all and learn from you all. That's all we have for now.
And until next time, we'll see you then. This concludes our episode of Fertility and Sterility Unplugged, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selena Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.
This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource in service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the host, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.
