NIPT false positive for T18

[Heartbrokenmama]

Hi ladies

I wanted to share my story in case anyone finds themselves in a similar position in the future and, like me, ends up frantically searching the corners of the internet for a positive story or a glimmer of hope to hold onto. This is my second pregnancy after a sudden and devastating full term loss earlier this year. It has been a very anxious pregnancy from the start. We opted to have NIPT (the SAFE test) done at 11 weeks and much to our shock and horror, a week later the result came back showing a high risk for trisomy 18. However at the 12 week scan the baby looked entirely normal with no soft markers for T18 at all. My combined blood test results (free hcg and papp-a) were also normal. For these reasons I was advised by the fetal medicine specialist that he suspected confined placental mosaicism. I was given the option to have a CVS right away but was advised that the results might be misleading given the possibility of placental mosaicism (more details on this below), and I was told it would be best to wait a few weeks until it was safe to do an amniocentesis.

After a long and torturous month of waiting I finally had the amniocentesis done earlier this week at 15+5 and the PCR results have thankfully come back showing normal results for chromosome 18 (they also looked at 13, 21 and sex chromosomes). We are awaiting the full karyotype results which take a few weeks, but given a normal scan and normal PCR results we are feeling very confident that this was a false positive and that the nightmare is behind us.

I’m sharing this story to make you ladies aware that although NIPT is generally quite accurate and false positives are rare, they clearly do happen and the only way to know for sure is through a diagnostic test like amniocentesis. I have done A LOT of research during the month we had to wait and wanted to share some of my findings in case anyone finds themselves desperate for any reassurance, because I know I was. NIPT is often marketed as having >99% accuracy, and while that is technically correct it can also be very misleading and disheartening if you get a high risk result. The key thing to keep in mind is that as great as NIPT is, it remains a screening test that can only give you a low vs high risk result, and it should NEVER be interpreted as diagnostic. The only diagnostic tests that can provide definitive answers are CVS or amniocentesis, although in certain circumstances even CVS can be misleading (more on that below).

NIPT looks at fragments of the baby’s DNA in the mother’s blood, so from my research I’ve learned that if you get a low risk result you can be very very confident that your baby does not have T13, 18 or 21. However things are a bit murkier than the test makers make them seem if you get a high risk result. Obviously the most common reason for a high risk result is unfortunately that the baby has the condition, but there ARE other very plausible reasons you could get a high risk result even when the baby is fine. Because the prevalence of conditions like T18 and T13 in the population is very low (> PPV for T18 = 63.6%

www.sciencedirect.com/science/article/pii/S1028455919302177

PPV for T18 = 60.7%

obgyn.onlinelibrary.wiley.com/doi/full/10.1002/uog.14792

PPV for T18 = 76.6% [lower and upper statistical limits 47.4-85.5%]

humgenomics.biomedcentral.com/articles/10.1186/s40246-020-00268-2

PPV for T18 = 62.96% [86.7% in advanced maternal age cases]

I’ve been advised that the most common reason for a false positive is vanishing twin syndrome, which is suspected in my case. Because of my history of loss I’ve been monitored quite closely with frequent scans since 6 weeks to ease my anxiety. At 8 weeks I had a high resolution scan and the sonographer noted a second yolk sac, which suggests there may have been a second embryo that never developed or died quite early in the pregnancy. 50-70% of early miscarriage has been attributed in studies to chromosomal abnormalities, so it’s very plausible that the vanishing twin had T18 and this is what the NIPT result was picking up. Studies have shown that DNA from a demised twin can remain in the mother’s system for up to 8 weeks and if a vanishing twin is suspected, NIPT should be done after 14 weeks gestation for more reliable results. Sharing below some literature I’ve found on this.

Fact sheet about T18 and possible causes of false positives: mydoctor.kaiserpermanente.org/ncal/Images/GEN_NIPT-T18_tcm63-1690053.pdf

www.sciencedirect.com/science/article/pii/S1028455919302700

Impact of vanishing twin syndrome on NIPT results:
www.researchgate.net/publication/322488527_Prolonged_duration_of_persistent_cell-free_fetal_DNA_from_vanishing_twin

obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.5817

pubmed.ncbi.nlm.nih.gov/30950018/

Other reasons for false positives include confined placental mosaicism, which is when there is an abnormal cell line in the placenta only. It is often suspected when NIPT gives a high risk result but the baby looks normal on ultrasound. The NIPT looks at fragments of DNA in the mother’s blood, which are marketed as “fetal” DNA but they actually come from the placenta. In the vast majority of cases the fetal and placental DNA are identical as they originate from the same embryo, but in cases of mosaicism when an abnormal cell line develops in the placenta, placental DNA does not accurately reflect the fetal karyotype. In these cases even CVS can give misleading results because it also samples the placenta. This is why I was advised to wait until it was safe to do an amniocentesis, despite the agonising 4 week wait that entailed, as an amnio samples the amniotic fluid and is therefore the most definitive method of testing fetal cells directly.

Some literature on choice of invasive test:
www.tandfonline.com/doi/full/10.1586/14737159.2016.1152890

obgyn.onlinelibrary.wiley.com/doi/10.1002/pd.4659

In my case, without sampling the placenta it’s impossible to know for sure whether the false positive was due to placental mosaicism or the suspected vanished twin, and all our doctors agree that it’s unnecessary to undergo another invasive procedure to find out, given the baby looks perfectly healthy. In all cases I am a high risk pregnancy after my previous unexplained stillbirth, and I will be monitored very very closely and most likely deliver a few weeks early via induction or c-section. Fingers crossed that this little bean continues to be healthy and we get to bring him or her home in the spring (we have chosen to keep the sex a surprise this time around!)

Finally, I will add that my experience with amniocentesis was much better than I expected. I was quite nervous about how I would feel during and after the procedure and was pleasantly surprised on both fronts. The needle looks huge and scary but the procedure itself was more uncomfortable than painful, there was a sharp scratch similar to getting a blood test as the needle went in, and then a very strange sensation of something moving around inside me, and some pressure when it was removed. My muscles around the incision spasmed a bit afterwards but overall it was much less unpleasant than some horror stories I’ve read online where people reported bruising, tenderness and heavy cramping for days afterwards. I’m very lucky to have had it done by an experienced fetal consultant who performed it flawlessly. It is frequently quoted that invasive tests carry a 1% risk of miscarriage but I’ve read that this is based on old data from the 80s, and technology has come such a long way since then. The procedure is now always guided by high resolution ultrasound so they can see what they are doing at all times and to ensure the safety of the baby. My consultant also made sure to only do it once the membranes had fully fused which apparently dramatically brings the risk down. Obviously so much depends on the skill and experience of the person performing the procedure, and you are entitled to ask the hospital or clinic where you are having it done for their specific track record. And obviously whether or not you have an invasive procedure is an entirely personal decision but I thought it was worth pointing out that from my research the miscarriage risks do appear to be overstated.

If you find yourself in a similar position to me, all I can say is that I wish you the very best of luck and I hope this research can help you navigate the rollercoaster with a bit more information. May you find the strength and courage to make decisions that are right for you in the face of indescribable stress and anxiety. This has been a very very traumatic for us, particularly after a sudden loss at the finish line earlier this year, but I’m so thankful the outcome of the amnio was positive and I hope your outcome is favourable like mine 🙏🏼🙏🏼🙏🏼 please feel free to reach out with any questions and I will try my best to answer based on my personal experience and/ or share more of the extensive research I have done.

@Umbuster I do wonder if these “unusual” situations are actually less unusual than we think, and it’s just that they didn’t have these kinds of tests in the past so people didn’t know what they didn’t know.. NIPT is relatively new so as more and more people use it I wonder if our understanding of how common or uncommon some things really are will change. For example all my doctors said that they think twin pregnancies are probably more common than we think (at least more common than the widely quoted 3% of pregnancies statistic) but many of them probably don’t survive as twins and by the time most women have their first scan the other embryo has vanished and it appears as a singleton pregnancy. I had my first scan at 6 weeks due to my history of loss, which is why we saw the empty sac but I think if I’d had it even a few days later we wouldn’t have seen anything at all and would never have known that there was possibly another embryo. Makes you think how little we really know!

I’m glad to hear that things are looking much more positive for you than a few weeks ago but what unnecessary stress this all has been for you. Good luck and keep me posted xx

@Heartbrokenmama Hi! I just wanted to give you an update. At 12 weeks, the midwife could still see the vanishing twin’s sac and placenta via ultrasound. I had my 16 week appointment (early anatomy scan) this week with the MFM and the ultrasound showed that my body had absorbed it all. Thankfully, the ultrasound also showed that the surviving twin is progressing nicely. My MFM told me that I can either redo the NIPT now that my body has absorbed the vanishing twin, I can do an amniocentesis to be absolutely sure, or I can do nothing and proceed. I declined the amnio and am still unsure if I want to do the NIPT. My MFM said she has zero concerns for Trisomy 13 or 18. But with Down syndrome you can not be certain unless you do NIPT or a diagnostic test like Amnio. Despite having great scores on nuchal translucency, presence of a nasal bridge, and the heart developing nicely, she said I won’t know for sure unless I proceed with the NIPT and then I can do an amnio if the results were bad. All of this is so scary. I never did the NIPT with any of my previous pregnancies and the one time I do, I have such an interesting case with a vanishing twin! I’m supposed to decide by tomorrow if I’m going to redo the NIPT bc I’m seeing my midwife then but I still have no clue if I should do it or not. My husband doesn’t think we should bc we are going to proceed with the pregnancy regardless but I really don’t want to find out at birth if the baby has Downs. Ugh. If I could go back in time, I would have never done the NIPT and I think maybe that’s my answer. Not to redo it bc I never did it before and thankfully the MFM was right last time too that the baby was okay. Sorry just thinking out loud now but also thank you so much for your kind words and support!

I have also experienced this but with Petau syndrome. I had the combined test at the 12 week scan and it came back high risk for Down’s syndrome 1:137. I was then offered the NIPT which came back positive for T13, Petau. When I went to see the consultant she said baby was looking pretty normal although the fima (upper leg) is measuring a little smaller than average which could be a soft marker for something. The consultant didn’t seem too concerned- but obviously we are after still very anxious after everything. She reassured us that she didn’t think the baby looked like it has Petau as they would expect to see noticeable abnormalities in the scan. We went for the amnio and it came back negative for all three.

my head is still spinning and fearful that it might be something else or something else is going to come up. I can’t feel fully relieved yet. I have a consultant scan at 20 weeks and the wait is killing me. This post has been so reassuring. There is so little out there relating to false positives.

thank you so much for sharing your stories!

@Jessicaflorence1 - I had a private scan with a foetal abnormalities specialist in London. I was just having private NIPT but when I told him I previously had an Edward's baby, he told me about his background and did a lot of checking for us. If you would find it helpful, I can dig out his name and pass him along.

That would be really helpful thank you!!

@Jessicaflorence1 - https://www.londonpregnancy.com/dr-fred-ushakov/

Hi, Hopefully this reply will also give someone some hope. We just went through total hell over the Christmas period after finding out that out NIPT results showed high risk for DS Trisonomy 21. However, the 12 week scan and normal NHS screening or combined tests showed Low risk. This was puzzling but we trusted the NIPT results more due to their higher accuracy rates. We were offered CVS at week 13.5 and results came back within 3 days. Luckily the results showed all normal and said they superceded NIPT results. We are still cautious as t
Nothing is 100%. Baby is due in June 24. Hoping all goes well. But I hope this helps anyone looking for a false positive story like we were for the last two weeks. 🙏.

Even though the thread is old, I’ll continue, giving some reassurance to women going through this.
I had a very low risk combined screening both with NHS and privately, all normal scans, but a high risk NIPT for T13. Waited until 16 weeks to do Amnio as in our case, CVS was likely to give the same results as NIPT. The Amnio quick and full results came back clear/normal. Amnio was done at FMC in London, completely painless and I didn’t feel a thing, not even when the needle went in. It was done by a specialist who is also a surgeon - I believe, the experience with Amnio depends on really who performs it. I was so scared and cried before the procedure and felt nothing.
It helped me mentally so much to find these false positive stories..