Trisomy 13 (and 18): is CVS fast result good enough for diagnosis?

[sciencefirst]

Following a positive Harmony (NIPT) test for Trisomy 13 and a positive QF-PCR result for Trisomy 13 (from a CVS), I've been trying to figure out what is the chance of the QF-PCR result giving a wrong diagnosis (holding onto hope!).

So far, the ultrasounds have shown nothing but a healthy looking baby (of course, it could be too early to see any abnormalities as I'm too early for the anomaly scan).

What I wanted to know from combined knowledge of the Mumsnet collective is, is my understanding below wrong? I am not a geneticist/medical person in this area and am learning as I go along. I write statements below, not to say that what I write is true, but rather how I understand all this stuff at the moment.

Having read some research papers, it appears that there is a fair chance of the QF-PCR incorrectly reflecting the chromosomes of the baby (again, to be clear, assuming that the ultrasound continues shows no abnormalities). So I should wait for the "long-term"/2 week/placental karyotype CVS result before making any irreversible decisions.

I understand that confined placental mosaicism (CPM), among other (much less likely) possible things, could give a misleading QF-PCR result. Although the incidence of CPM is estimated at 1-2% in all pregnancies undergoing CVS (i.e. including a whole lot of negative QF-PCR results), the incidence of CPM seems to be significantly higher for T13/T18.

Exactly how high is not certain because the absolute numbers diagnosed of each of these conditions is small (thus there is a random sampling error). But it could be 5-22%. This is too high for me not to wait 2 weeks!

QF-PCR (and also the Harmony/NIPT tests indirectly) from CVS uses a sample from a layer of the placenta (cytotrophoblast) which can have e.g. Trisomy 13. The other layer of the placenta (mesenchyme) may not have T13; the 2-week result looks at that layer. If that is the case, it is most likely that the baby does not have T13. Or the mesenchyme layer may also have T13, but the baby itself may not but this is less likely. Whether or not the fetus has T13 is determined via an amniocentesis.

e.g. Table 2 in www.tandfonline.com/doi/full/10.1586/14737159.2016.1152890

shows that in 23% of the "fast" CVS results (wasn't QF-PCR but something that tests the same cytotrophoblast layer as QF-PCR) which were positive for T13, the baby didn't actually have T13. (23%=(5+23)/120).

This study: bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-021-03570-6

was focused on women age >35 years who had a positive NIPT and no structural abnormalities showing on the ultrasound. It showed 72% of women with a T13 NIPT result and in which the "long-term" result was determined, actually had a healthy baby (72%=13/18).

In this paper: obgyn.onlinelibrary.wiley.com/doi/10.1002/pd.4659

the authors say at the end "In the case of a high-risk [NIPT] result for trisomies 21 and 18, CVS can be considered but with the caveat of a 2 to 4 % risk of an inconclusive result. In the case of a high-risk result for monosomy X and trisomy 13 amniocentesis would appear to be the appropriate test, especially in absence of sonographic findings. "

While these percentages are all based on small samples and probably different procedures, different groups selected for analysis, etc, and the percentages will thus vary, the broad message to me is that: you must wait for the karyotype/2 week result for the CVS for T13/T18.

The reason why I am asking for your input is that the midwife assured me that the QF-PCR results were very sure. But the academic literature is suggesting a different story...and I'm driving myself crazy here...

From my understanding, there can be false positives from CVS, as described in the papers you've mentioned. CVS is sampling the cells from the placenta, so if there's confined placental mosaicism then that can come back as a positive result when the baby might not be affected. Given the importance of making the right decision for you and your baby, you might want to get amniocentesis, which is considered to be more accurate than CVS (although does itself carry a small risk of complications including a small risk of miscarriage). If your instinct is telling you to wait and get more information, I'd trust your instinct - plus, you have to live with whatever decision you make, so you need to be confident that you've made your decision based on the best possible evidence.

Thanks, @Scirocco, that's how I feel about it...I want to be as sure as you can be. Once/If there are typical T13 abnormalities on an ultrasound then I would accept the CVS result as true.

Does anyone know if I am likely to get a detailed diagnostic ultrasound and amnio on the NHS on request (given I've already had a CVS on them)? Or would I have to go privately for that?

I had a TFMR a few years ago because my baby had T18. It was obvious from the 12 week scan that there was a problem and the CVS confirmed it.

In my experience, the hospital would have done anything I needed them to in order to make my decision. They were very understanding and empathetic so I’m sure if you explain your concerns, they’ll be happy to rescan and retest.

Thanks, @Waggily, that's very reassuring to hear.

@sciencefirst I’ve recently had an amnio following test results and a cleft lip diagnosis. I had the test through the nhs 48 hours after initially requested it with the midwife. Couldn’t fault it. The first set result came back within two days which were clear but we are still awaiting the full chromosomal report. Bed rest for nearly 3 days after it and have had no issues since xx

Sorry you are going through this @sciencefirst. I had a false positive with my second DC who was diagnosed with Turners syndrome via.CVS. They did say it was possible the anomaly was confined to the placenta but the only way to confirm was through an amniocentesis. I was offered one but declined as we had decided to keep the baby either way. All scans were normal and sonographers did express surprise with my CVS diagnosis as couldn’t see any evidence of Turners
When she was born it was confirmed via blood tests she did not have Turners syndrome so anomaly had been confined to placenta

Thanks for sharing your experiences, @Overtherainbow2021 and @Birthdaysybother, it is much appreciated.

I also read this from a world expert on confined placental mosaicism:

"(1) All fetuses with T13 have major US scan alterations already visible in the first trimester - if the fetus looks normal the T13 result is highly likely to be due to (i) a mosaicism in the placenta, or (ii) a low level mosaicism in the fetus (mosaicisms may not be sufficiently represented in fetal tissue to cause visible anatomical anomalies) or (iii) to a vanished twin.

(2) The application of QF-PCR on chorioni villi has different intrinsic limitations related to mosaicism detection the most relevant one of not having a sufficient resolution for mosaicisms (it cannot distinguish between 100% trisomy vs high level mosaic - e.g.: 70% trisomy vs 30% normal cell line) and the combined Long term culture of placenta may provide a fully abnormal T13 result but the fetus may still be normal or mosaic.

Based on this, it is not advisable to perform a CVS and analyse it with QF-PCR+Long term culture. You could get an abnormal result from both analyses but, nevertheless, there would still be a high chance of a normal baby (the US scan is highly trustable if conducted by 'good hands and good eyes'! ).

So, in case of T13 NIPT result, relying on an abnormal T13 result based on CVS analysis only with a normal US scan is not advisable."

@sciencefirst

Hi there, my partner and I are currently position to you.

CVS indicated T13 however fetus appears normal on scans.

Curious to know how you got on? We're you able to confirm it was CPM in the end?

@babyonboard90

In the end, it wasn't good news. I had a CVS done and waited for the 2-eeek result which was again positive for T13. At that point, I asked for an ultrasound and an amnio. And the ultrasound showed severe defects which were consistent with T13. I did the amnio anyway and was then confident in a 100% diagnosis of T13 (I just waited for the fast result at that point, given the ultrasound showed so many things severely wrong). I had a medical termination, at 18 weeks at that point.

However, as long as the ultrasound is normal then there is a good chance that baby is Ok. That is what my reading of research papers on the topic told me. International best practice is do an amnio as that avoids the chance of wrong diagnosis due to CPM. And CPM is much more likely for T13 and T18 than for, say, T21.

In my case, it did not turn out to be CPM but I am only one experience. And looking at my wee baby after he was born, he looked almost perfect to my untrained eyes. So I was glad that I had the certainty of the amino and ultrasound, both together for my peace of mind (not that I was happy because who wants to be in that situation?).

Although the push is to get a CVS done as you get a result earlier and termination will happen earlier with a shorter time to worry from the mother before the termination, if there is a doubt about the diagnosis (which there was for me, given the normal ultrasounds I had up to and at 14 weeks) then for my long term peace of mind, I preferred to wait until I myself was 100% certain (the doctor and nurse thought the fast CVS was enough even though NHS screening guidelines say otherwise when there is a normal ultrasound).

There was a high profile case in Dublin concerning a baby diagnosed with T18 on the basis of a NIPT test, followed by the fast result of a CVS showing T18. Ultrasound was normal. The couple terminated but then the 2 week CVS result was normal, which would strongly indicate that the baby was normal (a type of CPM ...there are a few types as you will see in the literature, depending on what layer of the placenta is abnormal and if the baby is abnormal or not). And the father was a consultant doctor, so even he did not know (not his field of expertise but still...).

I wish you the best...it is a very stressful time for you. There is no right decision, just a decision that you individually can live with for the rest of your life. That is what I decided.

@sciencefirst

Thank you so much for sharing your story. That sounds absolutely earth shattering and I'm sorry things didn't go better for you. Your post was one of few we have been able to find on the Internet that was similar to ours, and was incredibly informative.

As you mentioned this is an incredibly tough time for us, we're doing our best to remain positive.

We have an appointment in 5days where we'll have another scan. I imagine we will also have the cultured CVS results (though doctor made no mention of this previously on the phone) and possibly an amniocentesis.

Our CVS was done due to an administrative error. Initially doctor said fetus had 1 in 2 chance of T21, so we agreed test. They realised the error after the procedure and risk of T21 went down to 1 in 5000. They apologised and agreed to test the sample anyway. 1 in 20,000 for T18 and T13.

We were angry but incredibly relieved, though the relief was short-lived as two days later Dr advised T13 was found in placenta. The sequence of events (I.e. we were never supposed to have CPM) is the only thing giving me hope. Plus the doctor did advise that it could be confined to the placenta, before we became as informed on the matter as we our now.

Anyway, we'll cross the bridge when we come to it. Thanks again for responding to my message. All the best.

@BabyOnBoard90

I think it is very good that your doctor is acknowledging the possibility of CPM. Mine seemed to think that I didn't want to accept the T13 diagnosis. Which wasn't true - it was simply that it wasn't 100% certain in my mind until the ultrasound and amnio showed it to be true.

In any case, from what the world expert on CPM said, as long as the ultrasound is showing normal there is a very good chance (it seems 50%+ from one research paper I read) that even if the 2-week CVS long term result is positive, the baby is still normal. However, there may be implications for the baby's development if the placenta is very abnormal - but on that, your doctor can advise you.

A wider issue is that, with the advent of mass NIPT testing, there will be more CPM cases picked up which wouldn't have been known about before. Of course, the absolute number is still small. But there should be more awareness among obstetricians of CPM and that it is more likely for T13 and T18, and rarer trisomies. The Dublin case and other things I have read indicate that awareness is not high.

Good luck! I hope it does turn out to be CPM for you and a very localised case at that.