When cell free fetal DNA isn’t

Fig. 1 U.S. NIPT Brands

Fig. 1 U.S. NIPT Brands

For years, I’ve been presenting at conferences on prenatal testing for Down syndrome, explaining how the new tests are based on cell free fetal DNA or “cffDNA.” Turns out I was wrong. Here’s why.

This past week I gave a poster presentation at the Annual Clinical Meeting for the American College of Medical Genetics (ACMG). There is where I learned I was mistaken about the basis for newest form of prenatal testing.

Poster presentations are where you stand in front of a poster and present on the information it displays. (I’ll have more on my particular poster later). One of the first conference attendees to walk up to talk about my poster was a medical geneticist that, we figured out, was stationed with me when I was in the United States Air Force. In talking about the newest form of prenatal testing, non-invasive prenatal testing (“NIPT”), he off-handedly mentioned, “well everyone knows cffDNA is really placental DNA.” Well, this everyone did not.

NIPT has received a lot of media attention, due in no small part to the private laboratories promoting their various versions of it. Currently, in the United States, there are four laboratories that provide NIPT: Sequenom, Ariosa, Verinata, and Natera. Figure 1 displays these laboratories’ respective NIPT tests in clockwise order, respectively. In the professional medical committee opinions and materials from the testing laboratories, where reference is made, often it is to “cell free fetal DNA.” So, I suppose I should be forgiven for not understanding that the DNA was not, in fact, fetal DNA.

Instead, it is placental DNA. Now, here’s where we time travel back to high school. Some of us may remember cellular biology: the nucleus, mitochondira, etc. When a conceived cell implants into the mother, the cell has divided into further cells that perform certain functions. There are the cells that go on to become the fetus; there are those cells that go on to form the placenta (these cells come from the group of cells called “cytotrophoblasts”); and, there is even other genetic material which performs the function of anchoring the fetal and placental cells to the cell wall of the mother (called “syncytiotrophoblast”). Figure 2 is a rendering of these various forms of cells.

Fig. 2 Implantation of embryo

Fig. 2 Implantation of blastocyst

It turns out, that almost all of the cffDNA found in the maternal blood stream actually comes from the DNA of the cells that form the placenta or perform the anchoring function, not the cells that form the fetus. Therefore, it’s not entirely accurate to use “cell free fetal DNA” when discussing MaterniT21, Harmony, Verifi, or Panorama-style non-invasive prenatal testing.

As a fellow conference attendee explained, this is a distinction without much difference; while it is not cffDNA, in his opinion, it was not that big of a deal to refer to it as cffDNA. And, perhaps it’s not. But, I would guess that expectant mothers would think differently on the accuracy of a test if it were explained to them that the test did not actually test fetal DNA, but instead was “cell free placental DNA.” And, based on one of the last presentations I attended, they would have reason for that different perspective on the test’s accuracy.

The last session’s speakers presented cases involving various genetic issues arising in the prenatal stage, including false positives and false negatives they had experienced with NIPT. It is for this reason—that there are false positives and false negatives—that NIPT was revised from NIPD, non-invasive prenatal diagnosis (and will soon undergo another name change).

In one of the presentations, the presenter explained how a patient had received a positive NIPT result that ultimately was found to derive from what’s called “placental mosaicism.” “Mosaicism” occurs in the case of triploidy where there is a triplicate of a chromosome in some, but not all, of the cells. In placental mosaicism, the placenta can have cells with triplicates of chromosomes while the fetus does not have any triplicate chromosomes in its cells. Indeed, the diagnostic test that can be performed in the first trimester, chorionic villus sampling (“CVS”), tests placental cells, and has returned results of Down syndrome even when the fetus does not have Down syndrome, because the particular placental cells tested had a triplicate of the 21st Chromosome.

The presenter on the false positive based on placental mosaicism concluded by saying that because NIPT tests placental DNA, the most it can ever become is as accurate as a CVS. While CVS is considered a diagnostic test, CVS results still have the risk, however slight, of returning results from a mosaic placental cell that is not represented in the fetus itself.

Placental versus fetal DNA may be a distinction without much of a difference when it comes down to the accuracy of the results. In the vast majority of cases, the results will be accurate for the fetus even when the test is of placental DNA. But, this is more than just a semantical difference—or, even if that is all it is—then there is a significant semantical reason why “fetal DNA” was chosen over the more accurate “placental DNA.”

Mothers will expect prenatal tests to be of fetal DNA, not placental DNA. If “placental DNA” were used, perhaps expectant mothers and general society would further appreciate how the newest wave of prenatal testing is, in most cases, not actually testing DNA from the fetus, but from the placenta. Using precise language would further make clear that NIPT results are, at best, highly accurate screening tests, but not certain enough to make any decision without first receiving a diagnostic test result.

Update: For more lessons learned about NIPT (including why it’s NIPS) click here.

Comments

  1. I am a patient who took the Panorama NIPT. I was high risk for Trisomy 13. An amnio later determined my fetus has 46 chromosomes — normal, no Trisomy 13. Looks like I have confined placental mosaicism (will be diagnosed once I deliver and the placenta is examined). It’s important for women to know that these tests are not 100% accurate and that CPM has cause a ‘false positive’.

    • Chelsie–your comment was well-timed as it arrived while I was at a conference giving a talk on the accuracy of the newest prenatal testing for Down syndrome and other aneuploidies. Thank you for sharing your experience.–Mark

  2. Here is my story. I am not sure what to make of it but if you can tell me what you think it will help me a lot. I am 31 and my wife 33. We got pregnant after an IUI. Now at week 10 the u/s showed a slight thicking behind the neck. The dr asked us to take Panorama test. We did that (at week 11) and after 3 weeks it came back inclusive for Trisomy 21 (others were negative). The dr says the report said “not enough fetal fraction”. I guess that means they did not have enough cells from fetus to test with. Panorama asked us to resend the sample so we did that (this is week 14 now). After a week it still shows inconclusive ! This time the dr says the report shows sample does not meet some metrics . And mind you we sent two vials of blood (not sure if they used both or not).Now we are going for Amnio at week 16 . My question is what is the precedence of this? What do we make out of it. Have you encountered any such case ? if yes what was the outcome? Thanks in advance !

    • By coincidence, Natera, the NIPS lab that offers the Panorama test, hosted a webinar on Tuesday entitled “The importance of fetal fractions.” The presentation made the point that low fetal fractions makes NIPS testing less reliable. A questioner asked what they do if an initial test is inconclusive. The response was they ask for another sample and they usually are able to report a result after the second sample. So, by using the term “usually” (or a word like that, I’m paraphrasing the response from memory), that would suggest that, yes, Natera has had second tests come back inconclusive. Because they didn’t speak to it, I do not know what they suggest in such a situation. Hopefully, you at least were not charged for the tests since you never received a result. Another consideration would be to see if another NIPS test could be done, e.g. MaterniT21, Harmony, or Verinata to see if one of those returns a result. Each NIPS lab uses a bit of a different testing method. One of the critiques from the professional organizations is that there is currently no data set by which to compare which of the tests is more accurate than the others because of the way each lab controls what information they release about their tests. Feel free to provide an update either here or privately to me via e-mail at mleach[at]downsyndromeprenataltesting[dot]com.

  3. I just took the amnio 2 days ago. My harmony test came back greater than 99% abnormal. I’m upset why my doctor sent me to do the prenatal screening in my second trimester instead of first trimester. Now that I’m about 21 weeks, I can’t imagine myself aborting my baby since I have already felt him move a lot. At the same time, dealing with a child with Down syndrome is very challenging. I’m so angry since I found out the non-invasive prenatal testings can be done as early as 10 weeks. This would make it so much easier for parents to abort if they feel the need to before feeling their babies move. I’m stuck in this dilemma. I’m hoping there’s a miracle that my harmony test was wrong by confirming it with an amniocentesis.

    • This is relatively new for our OBs in the US. Im 14 weeks and mine didn’t know about it until I asked for it. The important thing to remember is that even if you HAD taken this test at 10 weeks, you would have had to wait until 15 weeks for an amnio anyways. A CVS tests the same placental dna as the cffDNA test you had.
      My first child had full (not mosaic) T13 and because two of these three chromosomes were attached to eachother, I have decided to DNA test anytime I am pregnant. I had a CVS with my 2nd child (healthy) and will be having the Harmony done tomorrow for the 3rd. I am 14 weeks.

      • Felicia, thank you for sharing your experience and reasons for prenatal testing. I hope the NIPS test provides the information you are looking for. I would be curious what Ariosa (and any other NIPS lab) would say about what their detection rates would be for not just T13, but the joined T13 in your specific situation.

    • I’m confused here. You do understand the baby is moving even before you can feel it right? That your baby is alive even before you feel it move or see it on an ultrasound. Do some research, watching In the Womb by National Geographic, might help. Life begins when sperm meets egg. I had an ultrasound last week at 9 weeks 3 days. The baby was moving. Yes. Shocker. The babywas already alive and moving and a heartbeat was seen and heard. My son is seven and that night he said to me “Mama! It’s so cool! Did you know I am already a big brother? Because that baby is already alive in you.” A 7-year old gets that but adults don’t seem to. It boggles my mind and makes me very angry more people don’t do the research and unnecessarily choose to make themselves God and end lives

      • tatevikt11 says:

        It’s a personal choice, and, surely, you are not entitled to judge others. I speak as one who is a lover of Christ.

      • I don’t think that this is the goal of this blog or comment board- to decide whether its wrong or right when there is no real answer, only a very hard, personal choice. It is no one’s right to judge someone in a heart wrenchingly difficult situation.

        • Victoria Miller says:

          Mark, I wonder if you would consider closing comments on this post that is over a year old. It keeps attracting questions that we all get notifications on that are usually expectant parents seeking answers that you keep needing to refer back to their doctors or genetic counselors for real answers on their individual cases. Just a gentle suggestion?

          • Thank you, Victoria. I apologize if the commenting is an annoyance. However, I am glad that readers still comment and ask questions on a post from a year ago. This post is one of the most often read on a daily basis, so I would like to leave comments open so that readers with questions may post them.

          • Victoria J. Miller says:

            Mark, my concern was the tenor of the comments right above me where I replied and wondering if the “space” left open was in some part attracting drive-by judgements. But let me try not to fix what is not mine to fix.

          • I always appreciate your input, Victoria. Thank you.

  4. These tests identify also the sex of the fetus. Is it possible to find that only from placental DNA?

    • My understanding is yes because if there is a “Y” chromosome found, then that would mean the fetus is a male, and the absence of a “Y” chromosome means the fetus is a female. But I welcome any links on this.

      • Hi- I will be 14 weeks pregnant on 12/28/13. I was just informed that my Panorama drawn at 11w4d resulted in Triploidy X. I was advised to immediately follow-up with a CVS. We are devastated. Are there cases of placental mosaicism of “triploidy x” where the fetus could still be healthy and diploid?

        • I will see what I can find, but I would recommend consultation with a genetic counselor.

          • Thank you- we absolutely will. I’ve been sleepless, scouring the internet for hope and information, and found this article. Granted they are case reports, but given this research is so new, with much to be learned, I will not ignore it, and wonder if the author’s deductions about placental/maternal mosaicism are true. See link
            http://pregnicare.co.il/Assets/articles/secondary%20findings%20from%20non-invasive%20prenatal%20testing%20for%20common%20fetal%20aneuploidies%20by%20whole%20genome%20sequencing%20as%20a%20clinical%20service.pdf

          • Thank you for the link to the article. Regarding your test results, did they report triploidy or triple X, also listed as 47 XXX? The impact of the two conditions are on opposite ends of the spectrum, with triploidy being incompatible with life while women with an extra X chromosome may live their lives unaffected. Another thing to keep in mind, a CVS also tests cells from the developing placenta, just as NIPS/Panorama does; therefore, CVS also has a risk of diagnosing a condition in the placenta, not the fetus. An amnio, on the other hand, is of the fetal cells. Having said all of this, I’m glad you will be meeting with a genetic counselor. If you need help finding one, the National Society for Genetic Counselors has an on-line search tool at this link.

          • Thank you for the info and link of counselors. Two of the four NJ university hospitals that I called, thankfully returned my call immediately. We are on our way to meet with the genetic counselor and have a CVS. Unfortunately, the results indicated Triploidy X (69 chromosomes XXX). I will probably need an amnio as well to test fetal cells, but will discuss this with the counselor. I have realistic expectations but need all the information available. I will definitely discuss the case reports of placental vs fetal chromosomal variation, and if this can even exist in triploidy X.

          • I hope you receive wonderful care.

          • Thank you- the genetic counselor was incredibly thorough. Most importantly, she informed us that our OB misread the results. It was indeed Trisomy X that was reported, not Triploidy X! We proceeded with the CVS to better prepare ourselves for whatever is actually going on with our viable, baby girl- thanks for the support!

          • Thank you so much for sharing and I’m glad you received thorough care. Misreading results is built into a process where humans read the results, but wow–what a misread! The Lettercase pre-test pamphlet refers readers for more information about Trismoy X to this link. I hope that proves helpful and wish you well as you move forward.

  5. I recently decided to have the Panorama test done, due to a slightly elevated risk for Trisomy 21 from our Nuchal Scan (1 in 405). The Panorama came back showing 96% risk for T21, from a fetal fraction of 4.6%. My husband and I were clearly devastated and assumed the worst given that all the research claims that they have 99.9% accuracy and 0% false positives. However, we have now received the results from our amniocentesis which have (miraculously!) confirmed that our baby doesn’t have T21 (or any other chromosomal problems). Natera have provided no explanation as to why this could have happened or asked to see my final amnio results. I’m not sure how they can get away with claiming to have no false positives when clearly I’m not the only person this has happened to.

    • Found this link in my search for information about false positives. The NIPT companies really need to provide better information about what their statistics truly mean. Im still waiting for my CVS results to compare with the Panorana, and may still need an amnio. However, I really needed more information about the Panorana (all nipt’s) and there is not a lot out there…

      http://thednaexchange.com/tag/nipt/

      • Thank you for sharing Stoll’s post. It is one that I’ve been meaning to comment on further and will likely do so thanks to your reminder. Another of her posts prompted a series analyzing the predictive value of the new prenatal tests, like Panaorama. That series is at this link. In addition to Stoll’s good work on this issue, your point is one that has been expressed by professional medical societies and in medical journals: that the accuracy of the new tests remains questionable because the test manufacturers control how and what information is shared.

    • In my recent reply to another comment on this post, I shared how you are not alone in your frustration and concern about how the new test’s results are presented. Professional medical societies, journals, and practitioners have all expressed a “serious concern” about the risk of misunderstanding non-invasive prenatal screening results as being more accurate than they really are. However, it is not in the labs’ business interests to suggest their tests are less accurate than they market them to be. 23andme recently had a class action lawsuit filed against it based on consumer fraud for alleged misrepresentations about its test results. Unfortunately, it will likely take a very bad situation before a patient is damaged enough that they will be willing to put themselves through the stress of a lawsuit for misleading information about the tests.

  6. I had an NIPT done last week; not sure of the name but it was through Kaiser Hospital in Oakland, CA. The results returned a 70% high risk result for Trisomy 18 based on a fetal sampling of 4.6%. I then had a level 2 ultrasound where the doctor indicated strong markers for Trisomy 18. I took an amnio today and am praying that the results return a normal chromosome result. My question is, with odds stacked against me with the NIPT and ultrasound, what are the odds that both are wrong? I’m currently 18 weeks pregnant and baby is measuring 18 weeks. Doctor stated baby appears to have brain cysts, clenched hands, abnormal feet, challenges with swallowing ambiotic fluid and small head and chin. This sounds so devastating!

    • I wish I could tell you precisely, but though I cannot, I hope you will have access to a genetic counselor who should be able to. Of the false positives that I’m aware of for NIPT, they do seem to be represented by more Trisomy 18 findings than others. The Trisomy 18 Foundation is a very good and compassionate organization. I hope you will seek them out should your amnio confirm the screening findings and they can support you now while you wait.

  7. At our 20 week ultrasound, our doctor saw a couple of markers for Trisomy 18. She recommended that we do the Harmony test first to see if we had a high risk. The results came back negative for Trisomy 18. (0.01% risk) Last week, we buried our baby. He was diagnosed with Trisomy 18. I don’t think these tests are as accurate as they claim to be and I wonder how many other false negatives are out there.

    • Brenda I am extremely sorry for your loss. I received a t18 diagnosis and awaiting amniocentesis results to confirm. My NIPT test said 70% t18. Do you mine sharing what the markers were? I have markers as well according to the dr – thickening in the right ventricular heart wall, small stomach bubble, small chin, close eyes. He also says both hands of the baby were clenched with overlapping digits. However, the hands weren’t clenched on the 12 week ultrasound. I’m 18 weeks and the baby is also measuring the same.

      • Hi Michelle, I’m sorry for all the worries you’re experiencing in your pregnancy with this baby. Right now the NIPT are used for screening purposes that then lead to a referral to maternal-fetal medicine specialist for further evaluation. I’m glad to know that amniocentesis is being done as that is the only current true diagnostic test that can give you answers about your baby’s genetics. The advantage of the amnio is also that it can go beyond just Downs, T18 or T13 to more rare chromosomal disorders or deletions or partials. I’m hoping with you that the amnio results are positive showing no problems. If a T18 diagnosis is confirmed, I hope you’ll find support with us at the Trisomy 18 Foundation at http://www.trisomy18.org.

        • Michelle, do you mind me asking what NIPT test your doctor used with you? Harmony? MaterniT21? others?

        • Victoria thank you so much for your response. Can you tell me (if you’re aware) of what other chromosome disorders would yield the type of markers as mine and is the outcome if fetal demise that of trisomy 18

          • Michelle, the outward features that can be seen on ultrasounds are shared by any number of disorders. I wish I could be more definitive than that, but the amnio will provide some answers to all these questions. Feel free to reach back out to me at vjmiller@trisomy18.org when you learn of the results.
            Victoria

          • Thank you dearly! This is hard because of everything I’ve read and heard of T18, except the clenched hands which wasn’t seen in the 12 week ultrasound (baby was waving) seem on the mild side, unless a hole in the heart can develop from a mild thickening of the right ventricular wall.

      • Michelle,
        At our 20 week ultrasound, the soft markers were plexus cysts (which they weren’t worried about), clenched fists and hypoplastic left heart syndrome. When he was born, there were alot more markers that they didn’t identify on ultrasound.

        • Brenda thanks for sharing that information with me. My amniocentesis results were given to us yesterday evening and it was positive for t18. Words can’t explain our devastation.

    • Brenda, my condolences for your loss. Thank you for sharing your experience, since I have not had many share about false negatives. The Trisomy 18 Foundation has featured recently some resources for grieving parents. I hope you will receive support as you feel guided to do so.

      • Brenda,
        I am sorry to learn of the loss of your little one to T18. And of the false negative, I know was especially upsetting and probably left you unprepared. Did you learn some other way of your baby’s diagnosis before birth? I do hope you will connect with us at the Trisomy 18 Foundation where you can share your loss with many other parents who have also lost their precious children to this devastating condition at http://www.trisomy18.org

        • Victoria,
          We had a couple of soft markers, (heart defect, clenched fists) but because of the negative result on the Harmony test, we thought we were in the clear. Obviously, we can never trust the Harmony test or any of the cell-free-dna testing again.

          • Oh Brenda. I know exactly how you feel as this is very close to my own story where we were “surprised” at birth thinking we were in the clear after having lost 2 previous pregnancies. But what that experience really drilled in my head was the importance of doing prenatal diagnosis and not trusting the screening tests completely.
            I know you wanted to be much more prepared to make choices in the best interest of your child and family — and you would have. You can’t help but feel like you put your trust in the wrong things. I came to feel that I couldn’t trust anyone (no thank you to those reassuring pats on the head that everything’s fine), and only HARD DATA could I trust. So yes — tests — and show me the results — that became my “take away.”
            So bottom line — only an amniocentesis can provide that HARD DATA today. And like you, I wish I had been able to KNOW in advance after a missed prenatal screening. Please know that you will find peace with all that happen over time. Meanwhile, I’m listening. If you’d like to email me you can reach me at vjmiller@trisomy18.org.
            Take care of your heart, dear.

        • I guess my whole issue is the fact that we didn’t want to do invasive testing which is why we did the Harmony test. I mean what’s the point of doing cell-free DNA testing otherwise. The whole hype around the Harmony test and others like it is that you can avoid doing invasive testing like the amnio and do the Harmony test first (because its 99% accurate)–and then if the Harmony test says you are positive (or high risk) you can then choose whether or not to do the amnio. But hey, if its negative or low risk, then the amnio is not as important. THAT is how it is promoted–THAT is how it is hyped to be.

  8. Hi. I’m 33 years old (my husband is 31 yrs old) based in India and we conceived using an IUI procedure at first attempt. I did my triple test and Nuchal translucency (1.5 mm) at 14 weeks, and I was shown to have 1:124; an increased risk for Trisomy 21. As per my Last Menstrual Period (LMP) I am at 17 weeks and 3 days, but scans at different centres show different weeks.. last scan 7 days back showed 15 weeks at the lab where I have scheduled a cell free DNA test on 10 Feb. It is highly expensive as they claim to send the samples to the US for testing. I am reluctant to do an amnio and wanted your input here. Should I go in for the CFF DNA testing and keep the faith that the result will be accurate (& favorable of course) or go in for an amnio directly? The results take 10 days in CFF and as per LMP I will be at 19 week+. Thanks for your help.

    • Mothers who intend to continue their pregnancies whether their child has Down syndrome or not, are increasingly relying on the CFDNA test results, & forgoing the risk of miscarriage associated with an amnio. Mothers who are considering termination are having the amnio in order to be certain that their child has Down syndrome or does not.

      • Mark I really agree with your comments. It was the amino positive results that led my husband and I to decide termination. Do you have any knowledge or resources about the success of IVF with pre-genetic screening testing on first cycle after an D&E? My D&E is scheduled tomorrow and my husband and I want to do this option when we try again in about 3-4 mos to be in a better position since we lost this baby to trisomy 18 at 19 weeks.

        • Michele, search the blog for PGD & you’ll find a post which has a link to ACOG’s statement on PGD. ACOG does not recognize it as an effective screen for aneuploidy, but I’m aware of it being done. I would recommend talking w/a genetic counselor or medical geneticist.

          • Thanks Mark – I can tell you that our Genetic Counselor said she felt it was a good idea and would put us in a better position when trying to conceive again.

    • And parents who want to be prepared for other conditions besides Down Syndrome (Trisomy 18, Trisomy 13, and sex chromosome trisomies, need to consider which screening tests can best give you that information. Other conditions than Down Syndrome also have a “marker” of increased nuchal translucency early in pregnancy. As is always the truth, only the results from an amnio are definitive in terms of diagnosis. Parents have to weigh the risk of how not knowing might impact their birth planning and choice of hospitals (some parents want to be at a hospital with high level NICU), risks of unexpected stillbirths against the risk of miscarriage from an amnio. Performed by MFM specialists who do amnio tests regularly, the risk of miscarriage is very low. But you can always ask your specific doctor how many miscarriages have occurred in their practice after performing an amniocentesis.

  9. Mark, thank you for this article and it’s excellent explanation of what these tests actually look at and where there are still challenges. I had the Panorama test done at 13 weeks. The genetic counselor called and said that I had low risk results for everything but Turner Syndrome. However, she and the other counselors were baffled by the risk result. They usually get a 99/100 on reports. My Monosomy X risk came back at >73/100 or 73%. Also, my ultrasound was excellent. No markers for any signs of monosomy/Turner’s. They suspect possible placental mosaicism but of course I would have to do an amnio for further confirmation.. My question is if any if the false positive/mosaic cases you’ve heard about had similar strange percentage statistical results on these NIPTs?

    • Laura–I am most familiar w/T18 readings resulting from placental mosaicism. However, from memory, I want to say there was a study by one of the labs that did report strange percentages for the sex based aneuploidies. I hope your GC will be able to counsel you further.

    • Hi Laura – my test came back at 96% chance of Trisomy 21, and the doctors came back with the same comment that it was normally >99%. Mine turned out to be a false positive. The amnio came back completely clear, so no sign of mosaicism either. My fetal fraction was 4.6%, which I believe is quite low and therefore may have impacted the results. Good luck – I hope the test turns out to be false for you too.

      • Charis-thank you so much for sharing your experience! Brought tears to my eyes and gives me some hope that the test might be wrong. So glad that everything worked out for you. :)

  10. Michelle says:

    I will start by saying that I have birth to a completely healthy baby girl four weeks ago. The 6 months prior were very stressful after a positive high risk for T18 on the Panorama prenatal test at 17 weeks.

    Needless to say we were devastated. We chose to not do an amnio as termination was not an option for us, and I didn’t want to put the small risk on my daughter. Sitting with anxiety was not easy but I took the time to prepare for the worst, educate myself extensively on these tests and T18, and ask friends to pray for us.

    We went in for monthly anatomy scans which continued to show her developing normal. We were sent for a fetal echocardiogram which was perfect. The doctor was hopeful. I was hopeful after reading several studies that show the strength of level 2 ultrasounds in diagnosing Trisomy 18. Most of these babies show at least two markers by 21 weeks.

    She was born on 1/30 small at 5lbs 2 oz, but appeared healthy. They took the placenta to biopsy it for potential placental mosaicsm (when the placenta can take on extra chromosomes but the fetus is fine). They also drew blood from the baby to karyotype her testing her chromosomes.

    This past Friday we got the call. Her chromosomes are NORMAL! The placenta did come back positive for T18. We are the very rare case of placental Mosaicism. Which also explains her smaller size.

    Looking back would I have done the test if it didn’t change the outcome and only gave me anxiety. In this case I was ok with it because I was prepared for the worst vs being blindside. I’m not sure I will do it again for future pregnancies. Likely I would only do it if there was a concern on ultrasound so I could be best prepared.

    I am so grateful, and truly see her as my miracle.

    I know placental Mosaicism is rare, but it concerns me that CVS sampling is considered diagnostic when triploids could be confined to placenta such as proven by this NIPT. There are likely unnecessary terminations after CVS that were false positives.

    I thoroughly looked over Natera clinical research and question why they chose to compare fetal fraction to CVS samples. They are essentially comparing placental tissue to placental tissue which would of course give high accuracies. Why didn’t they compare fetal fraction to amniotic fluid?

    Ideally it would be great if they could refine this test to truly test fetal cells. Until then, there will always be inaccuracies.

    • Thank you for sharing your experience, and your point about comparing fetal fractions to amnio versus CVS is a good one. Companies like Cellscape have been working on identifying whole fetal cells in the bloodstream to provide a more accurate non-invasive prenatal test. I’m glad your daughter and you are both doing well.

      • Michelle says:

        I’m “assuming” the FDA is aware of this “glitch” before they approve these tests.

        • The tests actually aren’t required to be approved by the FDA because they are “Laboratory Developed Tests” or “LDTs.” I’m not sure of the regulatory justification, but LDTs are not required to have FDA approval.

      • My understanding is this: Fetal cells can remain in the mother for years, even decades. Placental DNA is gone from the mother within weeks after giving birth. Therefore, only by looking for placental DNA can one rule out any influence on test results due to the fetus’s older siblings.

        • That may be the case, but at the same time, testing placental DNA is not necessarily testing fetal DNA and if expectant mothers appreciated that, they would have a more accurate understanding that NIPS remains a screening test, not diagnostic.

          • I suspect (hope?) that the education is something that is evolving and improving. Though the first time I heard of these tests I was told it was testing the fetal DNA, once I actually spoke with the genetics counselor it was made clear to me that it was testing the placental DNA. (And, truthfully, I’d already discovered this fact through google anyway, because I had many weeks in between first learning of the test’s existence and having it done, and I was really intrigued). Every thing I’ve read about it or heard about it (except for that initial intro to the test’s existence) has made clear that it is a screening and only CVS and amnio are diagnostics. That was gone over extensively by the genetic counselor.

          • I’m glad to hear you received the recommended counseling. Hopefully more will, as well.

  11. Hi, I took the Harmony test at 14 weeks 5 days and got a very strange result of 15% for chance of T21 (5.1% of dna). Neither Ariosa or the fetal medicine doc could really explain this and they did not suggest retesting. The doc suggested amnio and we have decided to do it around 32 weeks (I am now 29 weeks). We have had no markers for anything this entire time, everything has always been in the normal range. This was confirmed again at the 20 week scan. I am so worried and confused. I haven’t been able to find any other instances of this happening online so I was wondering has anyone ever heard of this?

    • I will see what I can find out for you Sheri.

      • Sheri–Ariosa calculates a “risk score,” which in most cases is >99% or <0.01%, but there are these “indeterminates.” An assumption can be made that Ariosa saw some increase in chromosome 21 but not at a higher probability level. This may occur due to mosacism (placenta or maternal in origin) or simply be a false positive. It sounds as though you are receiving genetic counseling, but if not, I would encourage you to talk with a genetic counselor further. I hope this is of some help.–Mark

    • Michelle says:

      Is the 5.1% referring to fetal fraction? Typically fetal fractions below 10% aren’t as good for analysis.

  12. Thank you Mark. Yes Michelle, if the fetal fraction was too low maybe that is what got me the strange result?

  13. Thank you, I guess we wait and see what happens after the amnio.

  14. Hi Mark, my first baby was born with T21 which was a huge shock for my husband and i as we had a low risk with NT scan and perfectly healthy looking baby with our morphology scan. Turns out she had a duodenal atresia and massive VSD and heart valve deformities and we spent the first 3 months of her life in hospital having heart and bowel surgery. I am pregnant again and had the panorama test recently and received a panorama low risk score of <1/10,000 (<0.1%) for all of the conditions tested. At first I was ecstatic but have become increasingly anxious over the past couple of weeks about the chances of a false negative result. I'm afraid to have an amnio and also feel a bit foolish doing this when i got such good result but i have a mistrust of tests after our first baby. Are you able to clarify exactly what the panorama risk score is telling me? Is it saying that they are more than 99% sure that my baby doesn't have any of those conditions? I have spoken to genetic counsellor but they keep reminding me that it's not a diagnostic test and although it's close to 100% it's not quite there. I'm trying to gather as much information about the panorama test as possible before i make a decision on whether to have further testing.
    Regards,
    Coreena.

    • Coreena, I would ask your medical professional to contact Panorama to answer these questions for you. Panorama has genetic counselors on staff to advise medical professionals on what individual Panorama results mean for the patient. I hope you get the answers you are seeking. Mark

  15. Just to update, I have just received FISH results and the baby is chromosomally typical. My doctor asked to take my blood again to re submit for NIPT on his own dime =) He is very curious as to why I got the result that I did. I don’t know if I will hear anything back about it but these tests are obviously fallible.

  16. Do you have anybody experience with verifi test?
    I am so nervous because my first 12week blood test was positive. I am going to verifi on Monday.

    • Being a screening test, there is no true positive or negative. Verifi, like other NIPS, will provide a more accurate odds assessment, but still has false positives & negatives. Invasive testing is the only way to receive a true positive or negative. I hope you have access to a genetic counselor who can advise you further.

  17. Aditi Gupta says:

    Hi Mark

    Why isn’t NIPT test named NIFTY provided by a leading Biotechnology firm called BGI Health from Hong kong mentioned by you ?
    Is the Information provided by you is limited to any specific Country ?

    • Aditi–while I will reference international news, studies, developments, I try to base my analysis of the NIPS tests on professional guidelines. Those I’m most familiar with are from the United States professional medical organizations, hence the concentration on the domestically-available NIPS tests.

  18. mas83@tamu.edu says:

    Hi Mark

    I read at least two posts of women whose genetic test for Trisomy 21, 18 and 13 (e.g. verifi test) came back negative, while it was later found that the embryo was triploid. Do you know why these trisomy tests would not pick up triploidy of the entire genome? It doesn’t make sense to me.

    Thank you

    • I’m not exactly sure, either. But I do know that Natera was promoting its Panorama test as being the only one to pick up triploidy based on it using SNPs technology while all others are using a form of sequencing. Dr. Skotko explained the distinction between the two types of testing in the webinar we did earlier this year, available at this link.

  19. Jamie Seidman says:

    Hi Mark,
    Your research is very insightful. After several miscarriages of babies all with chromosomal issues ‘not compatible with life’, I am 12 weeks pregnant with what appears to be a chromosomal typical male. We did the nuchal test and the Panorama test and both came back fine, however, my fetal fraction for the Panorama was “alarmingly” high according to my Dr. (25% at 9 weeks) and my papp-a was on the low side. They now think I have a serious problem with my placenta, will have pre-eclampsia or BOTH. What other tests can I have or is there anything I can do besides “wait and see”? I’m so scared of losing another baby.

    Thank you.

    • Jamie–my sympathies for the stress associated with your test results. For screening purposes, you’ve had the ones I’m familiar with for suggesting issues with the placenta. I would recommend you discussing your concerns with your OB and possibly ask for a referral to a Maternal-Fetal Medicine specialist. I hope these results are not indicative of any true issue and that you have a healthy pregnancy.

    • Have you been tested for Antiphospholipid Antibody Syndrome?

      • I was after my second loss and came back negative. Pretty much chalked it all up to “bad luck and bad eggs”.

  20. Well You confused me for sure .. and surely many others too . If the whole basis of Harmony test for CFF DNA is really testing Placental DNA (DNA from Cyto and Syncytio Tropb cells) and not the fetal cells (from inner cell mass) the why would any one ever do that in first place?? We are not interested in knowing the anomalies in mother or dad? we are curious to know whats going on with the fetus. Are you sure that there is NO FETAL DNA ever analyzed in harmony test ? and all the results we get if for incorrectly estimated maternal/placental DNA ? If you say yes , then I would go ahead right now and file a lawsuit against this scientific fraud /scam of harmony test since then its is misleading..
    Pls reply and clarify

    • Vijay–it’s the same dynamic as chorionic villus sampling (CVS). CVS tests the chorionic villi from the placenta that contain cells with maternal DNA and cells with fetal DNA. The labs try to distinguish one from the other and then report out the results as though they are from fetal DNA, which most often they are. However, they can incorrectly identify fetal DNA when it is actually maternal/placental DNA, hence why CVS has a higher false positive rate than amnio and why NIPS tests have false positives and false negatives. The confusion is that non-invasive prenatal screening is perceived as testing fetal DNA. If more understood it is testing DNA that could be fetal DNA or could be placental DNA, then more would understand why it remains a screening test and however NIPS’ accuracy rates are represented, they are never diagnostic.

  21. Hoping you are still replying. We received results for our harmony test indicating that there is a 36% chance of xxy. Here is the confusing part- we did ivf with ccs to avoid chromosome abnormalities as I have a history of losses. How is this possible? Which is more accurate?!?! We are meeting with a genetic counselor and are on the fence about an amino as we wouldn’t terminate for something like xxy.

    • I am still replying. From your message, you went through an IVF cycle where there was comprehensive chromosome screening (ccs) to screen out embryos with genetic conditions, but, yet, your Harmony test reports a 36% chance your child has XXY. XXY is an aneuploidy. The American Congress of Obstetricians and Gynecologists (ACOG) have a committee opinion on preimplantation genetic diagnosis (PGD) that emphasizes PGD has not been shown reliable enough to screen for aneuploidies. CCS is not exactly PGD, but this may explain how an aneuploidy like XXY may have not been detected. That said, appreciate that 36% still means more likely than not your child does NOT have XXY. I would encourage you to discuss these concerns with your genetic counselor. I would also review any informed consent form you signed prior to undergoing ccs to see if you were advised of the chance that aneuploidy may not be detected. A link to the ACOG committee opinion is at the end of this post.

    • Joeysmom says:

      I’m no expert by any means, but I’ve read a lot on placental mosaicism after dealing with my own experience… Maybe this is what’s happening here. I would imagine that the direct genetic testing of your blastocyst/embryo would be more accurate than placental cell extraction from your harmony test. Good luck to you! My nips and cvs showed xxx, but we skipped amnio. Getting a karyotype after birth.

  22. Hi Mark Leach, me and my husband did a harmony test. I am 33 years old and DS results shows good negative results. However, the x, y analysis shows a 8% chance of xxx baby. We would like to seek your opinion on this result and what does it mean? Is it a high enough risk to go for amniocentesis test? We are so worried and torn apart as amniocentesis test carries a risk of miscarriage as well. Kindly reply soonest possible.

    Thank you. Joanne.

    • Joeysmom says:

      Hi Joanne- I closely follow this thread and couldn’t help but respond to your post. “DS” is dear son, no? Baby boy? If so, that XXX cannot be your baby boy. If you are having a boy, I would suggest doing a karyotype on yourself. My friend just had her baby two weeks ago; harmony test at 11 weeks showed XXX. The lab actually overlooked the presence of the Y! She had a gender reveal party for her baby, thinking it was a girl with xxx. Turns out, her baby was a boy! She tested herself- SHE was the XXX. Went 36 years without ever knowing she had an extra chromosome, and only learned by accident. (Fyi- she is married, two children now, has a masters degree, and lots of friends- including me.) Just thought I’d share this- it’s a nice positive outcome of how high-functioning these girls can be!

    • Joanne–first, I would recommend you be referred to a genetics counselor if you haven’t already. This is what is both recommended by professional guidelines, and is just best practice as they are the ones trained in counseling couples weighing the decision of whether to pursue further testing. That decision is determined by your values and what goals you have for the testing and your pregnancy. Secondly, while still a relatively low chance for XXX, you should have received information about the condition. If you didn’t, visit this link, which the National Center for Prenatal & Postnatal Resources includes in its resources for sex chromosome aneuploidies. Third, if possible, I would ask the genetic counselor for the opportunity to visit with a family raising a daughter with Trisomy X. Again, this is what is recommended and is best practice. Thank you for reaching out. — Mark

  23. Hi Mark
    Really thanks for your quick reply despite it being a sunday. I read that there are high chances that harmony test may not be very accurate with xy analysis, even through its almost 99% accurate with determining the gender of the baby. Is that true and so u have any statistics on that base on your experience?

    Also we would like to find out what is the typical kind of results for xy analysis harmony test would produce? We have done extensive research but it seems that most people would stop at testing for T21, 18 and 33, and would not go on to opt to test for xy analysis via harmony test.

    Would again appreciate your feedback on our 2 questions again.

    Thanks
    Joanne

    • Joane–my apologies for the tardy reply. You are correct regarding the accuracy rate for sex chromosome aneuploidy (SCA). Because the published studies have been of small sample sizes, the professional guidelines do not recognize the NIPS tests for testing for SCA. I’m not sure how to answer your second question about what the typical kind of results Harmony has for xy analysis. But, I think, related to my answer to your first, is that there simply isn’t enough data published of a sufficiently large sample size to show what “typical” results would be. I hope that helps.–Mark

  24. Hi Joey

    DS we meant down syndrome.

    Regards

    Joanne

  25. What about reports on False Negatives? Have there been many? I am 39yo and had my Fetal DNA blood test taken at 10.5weeks along with my NT scan at the same time. My NT scan showed normal with a low 1.42mm neck measurement. Tech said everything looked good. My MaterniT21 blood test came back 3-Negative. We were comfortable thinking everything looked good. My only concern comes from doctors letting me know that these tests are only 99% accurate and only an amnio is 100%. I am now 16 weeks pregnant. At 14 weeks I had a fetal echo ultrasound performed (my last son was born with undiagnosed TGA) and doctor said heart looks good “so far as it’s still so small”. He was the first to bring up the fact that the MaterniT21 is only 99% accurate and amnio is the only “proof”. He made me concerned thinking I should go for the amnio. To add to that at my 16 wk OB appt I asked my OB and she also would not allay my concerns and just said there have been false negatives as well as postives and amnio is the only 100%. Instead of reassuring me, they are raising my worry level. Here we thought we are “in the clear” with a 3-negative MartniT21 result and a “normal” NT scan. I worry about doing an amnio due to the risk of miscarriage. I am now more confused than ever. Can anyone allay my fears or have there really been many false negatives MartniT21 along with normal NT scan? I don’t know if I should go for the amnio or not with the miscarriage risk!

    • There are false negatives, but they are even rarer than false positives with the new blood test like MaterniT21. More and more women are choosing to rely on a MaterniT21 or similar type test result showing the pregnancy is not indicative of having Down syndrome than risking a miscarriage with an amnio or CVS. I would ask your OB for a referral to a genetic counselor to discuss your concerns. Genetic counselors are trained in counseling expectant women on the probabilities with genetic tests and how to make decisions consistent with your values.

      • Thank you so much Mark for your quick reply! What you mentioned, that false negatives are even rarer than false positives, is what I was hoping to hear but of course none of my OB doctors could directly say that. I am setting an appointment with a genetic counselor just to allay my concerns. Thank you again!

      • Mark,
        I am wondering if you would be willing to weigh in on my situation. I am currently 17+2 weeks pregnant with my 2nd child at 31 years old. I am high risk due to an autoimmune disease and my MFM specialist offered Panorama testing at my 13 week NT ultrasound presumably because he thought it was more accurate than the first trimester screen. He did not indicate any concerns with the NT measurement which were in the 1.7/1.8/1.9mm range. The results came back during my 14th week as “no fetal fraction” and they suggested a retest. I had the blood work (and husband the cheek swab) redone at 16+1 and received word this morning the fetal fraction was 2.2% and yet again too low for results. The nurse proceeded to draw for a third Panorama test today (17+2) but I don’t hold out much hope of a result as I’ve read the fetal fraction increase is only about 0.1% per week at this point. I was under the assumption that low fetal fraction in and of itself does not indicate any concerns for the health of the pregnancy. Where I am now concerned is that my primary OB called and indicated that I need an amniocentesis because the continued low fetal fraction somehow indicates a problem with the pregnancy. I have not had additional screening tests as we have put all our eggs into the Panorama basket as it is. Any thoughts on whether my OB is just proceeding with an abundance of caution or whether low fetal fraction at 17 weeks means there is something more likely wrong with this pregnancy?

        • You are correct that with that low of fetal fractions NIPS results are unreliable. However, I’m not familiar with low fetal fractions being an indicator of concern about the fetus’ health. You mention that you had an MFM specialist who offered Panorama but that your primary OB is the one recommending an amnio. If those are not the same person, I would suggest speaking with your MFM specialist to see what he or she thinks. I would be curious if your OB has any studies that show a concern about the fetus’ health where there are low fetal fractions in the mother’s blood. Whichever route you choose, I hope your pregnancy progresses well and that this does not cause too much anxiety for you.

  26. I want to leave my story here. When “false positive panorama results” are googled this site/post is #2. I am 36 years old. I have had 9 pregnancies, 3 living children, one on the way, and 5 miscarriages. I took the panorama prenatal blood test at 10 weeks. It came back with a fetal fraction of 4.4% and a 66% chance of trisomy 21. Our genetic counselor had only seen one other case that was not 1% or 99%. We opted for a cvs that failed because no villi were seen in sample. So 3 weeks later we did the amnio. Fish results normal male karyotype. Full results the same. Baby has normal amount of chromosomes. When asking everybody from panorama, ob, high risk ob, genetic counselor. Nobody seems to be able to explain the number 66%. This definitely is a screening test and no way near diagnostic. I wonder as time goes on how the stats will change with a bigger sample. Thanks so much for this post. Hopefully somebody will read my comment and feel a little hope.

    • Thanks you Amanda for sharing your experience. I share your hope that expectant moms will be counseled & understand that these new tests remain screening tests, with false positives & false negatives. Congratulations on your new baby.

    • I am hoping and praying that I will be a false positive. Had the harmony done at 13 weeks with a positive for T21 result at 14 weeks. I’m now 15 weeks waiting for one more week for my amnio on the 22nd. I am scrounging the internet for hope in the form of false positives. Thank you for making feel a little better.

      • Your chance of having a child with Down syndrome is informed by your age and the Harmony results. See the post here to find where your age is on the graph showing how a “positive” NIPS result can mean only a 40% chance if you’re in your 20′s or a 50% chance if you’re in your early 30′s.

        • Thank you so much for replying my age at conception was 39 and I am currently 40.

          • Then, according to just the number crunching, you may have a 10% chance of having a false positive. However, I hope you have received genetic counseling to discuss your personal background and likelihood. I further hope that your amnio goes well and you receive the care and support from your medical team no matter the result. Feel free to check the Prenatal Resources tab when ready and if applicable.

  27. I had the Harmony test because of my advanced maternal age (42). My test came back with a 20% chance of Turners Syndrome. I had an ultrasound completed and met with genetic counselor, but opted not to have amnio because I did not want to put the baby at risk. Genetic counselor seemed to think that there was a low risk because there were not physical indicators of Turners on the ultrasound. We had blood cord tested at birth and there were 46 XX chromosomes…so no Turners. For anyone reading this who may have the same test results as me, please try not to stress over test results.

    • Thank you for sharing your experience. The professional medical organizations do not recognize any NIPS test for identifying the sex aneuploidies because all published studies have been of populations that are too small. While your encouragement is appreciated, studies show that prenatal testing increases anxiety and, interestingly, this increase happens no matter the result. This is due to the understanding that there are false positives and false negatives.

  28. Hi I am 41 y/o pregnant with baby no3. Nuchal looked fine with adjusted risks= 1:1201 T21 and 1:2148 for T13/18. I had harmony test offered for raised background age-related risk. Yesterday I was called to let me know that the Harmony test result came back with 14% risk for T13 which is considered high risk and offered CVS which I had last night. I am awaiting the results in the next 24-48 hours for PCR and the rest of the results will follow in 7-10 days. I am not sure what to make of these results? The sonographer and consultant took further measurements which showed all organs, brain, eyes, kidneys, heart, limbs to be totally normal so far. What is the likelyhood of this being a false positive. Harmony state 0.1% false positive? How can everything look normal and there be such a big chromosomal abnormality.

    • Naila–it’s tough to say what a 14% chance for T13 means from a Harmony test. Harmony has published results showing an ultrasound indication prior to a Harmony test makes its test more accurate (see Poster 603 at this post), but I haven’t seen the converse, i.e. negative ultrasound results suggesting a Harmony test is more likely negative. That said, with the nuchal adjusting your probability upward from your baseline maternal age, it would seem that even a 14% chance means you have a greater chance for a false positive than a true positive. Given that you’ve had CVS to confirm, I hope you’ll report those results. Regardless of the CVS results, I hope you will have the opportunity to meet with a genetic counselor to further counsel you on these test results.

      • Thank you so much for your reply. This is very much appreciated. I will definitely report back with results. I am at HBR so have received flagship support and fully expect to be guided through the results and consequences. The staff were rooting for me hoping that it would be a false positive. They reviewed all the results and images over and over. Absolutely nothing to point to any major abnormality.

      • Hi Mark,

        Just got a call from the unit today. All clear on CVS for T21, T18 and T13. They also tested for CF and that was -ve also. So I will await the culture results but I can now breathe a sigh of relief.

        I am wondering if the results might have been affected by my SLE? I have anti Ro and ds DNA and ANA +ve. Not sure if that can affect things?

        I shall just enjoy the rest of my pregnancy now and happy with whatever outcome.

        Thank you for your help!

  29. I’d love some of your expertise help, Mark. I’m 23 weeks along, Harmony test came back 99% positive for Tri 21. In fine print it says the results are based on the fetal DNA (which I know is placental DNA), as well as the mothers age (I’ll be 39 when my baby is born), and the results of the ultrasound (which showed no nasal bone–though we could see it when he moved, he was very active! and, a calcium deposit in his abdomen). It was explained to me that when they gathered the fetal DNA, there was some extra material around the 21st chromosome, then they looked at the results of the ultrasound and automatically said high risk, 99%. I’m having an amnio next week just to be sure (hopefully) and for some peace of mind. We would never consider aborting, but want to be prepared as to how to raise our child and care for him in the best way if he indeed has DS. (Also, this is my 7th pregnancy, and they explained that the blood test collects fragments from not only me and my current baby, but also DNA fragments from all past babies). My baby’s DNA was 14.4% of the DNA collected. I have tried to get answers about the percentages are factored into the total risk percentage (the test itself, mother’s age, and ultrasound). The Ariosa clinic was unhelpful on the phone, refusing to answer any questions, and would only speak to our Doctor’s office. I had our Doctor’s nurse call, which she kindly did and still we did not get a clear answer about general percentages of these 3 factors which make up the final result. I think there should be more clarification as to how exactly the result is determined! Your thoughts? Thank you!

    • I agree that there should be more clarification on how exactly the result is determined–and it’s not just me and you, but every professional society that has issued a statement on this new testing has called on the labs to be more transparent in how they arrive at their results and what their results actually mean. That said, from your description and my understanding, all screening tests take your baseline chance of having a child with Down syndrome based on your age, and then run the findings of the screening test–an ultrasound, blood sample, etc.–through an algorithm to determine your recalculated probability of having a child with Down syndrome. Based on your age being 39 and the Ariosa test coming back 99% positive, then your probability is actually close to 90% chance for having a child with Down syndrome (see this post here). You still have close to a 1-in-10 chance of not having a child with Down syndrome, so I’ll be interested to hear what your amnio results are. If positive, I hope you will receive a copy of the Lettercase book (which Ariosa has provided to the doctors offering its test), be referred to a genetic counselor, and receive the contact information for your local Down syndrome support organization–all 3 things recommended by professional guidelines.

      • Just wanted to share that my amnio confirmed tri 21. We were hoping to prove the Harmony test wrong, but oh well! We are preparing the best we can for our sweet little guy to arrive and hope to help him have the best life possible. I actually believe it will be a blessing to our family. We will learn so much, meet people we never would have met, have experiences we never would have had, etc. And, our children will learn to be more compassionate and sensitive to those with special needs.

        Since I know you have a daughter with down syndrome Mark, I’d appreciate any advice you have. Things that have really helped your daughter, etc. And, what is your opinion of stem cell treatments for DS? I’ve heard it can help improve memory, cognitive function, movement, etc. Thanks so much! :)

        • Kristy–I appreciate you sharing your test result and your outlook on welcoming your son. I would recommend Diagnosis to Delivery and Your Loved One is Having a Baby with Down syndrome. These resources were written for moms such as yourself who are continuing after a prenatal diagnosis and address the myriad of issues expectant moms experience. In my personal experience, the greatest source of support and information which helped my wife and I was our local Down syndrome parent support organization. We were right before the ubiquity of social media, and I know moms now also find on-line support very helpful. I would recommend connecting with the Down syndrome pregnancy board at babycenter.com–one of the moderators is the co-author for Diagnosis to Delivery–and the Down Syndrome Diagnosis Network. I hope these help.
          As for what has directly helped my daughter with her development, we were fortunate to have a very good team of early intervention therapists providing physical therapy and developmental intervention therapy within Juliet’s first weeks, then adding occupational therapy and speech therapy by 6 months. We also had a nutritionist for a focused time when Juliet was having some digestion issues. Through our local group, we received new parent support through new parent monthly meetings. When Juliet turned 1, we began adding Nutrivene’s vitamin compound to her food and did that for about a year. Whether that had an impact on her development is difficult to say, but our nutritionist reviewed the ingredients and said it wouldn’t hurt her. I must plead ignorance on stem cell treatments for DS and invite you to share what you learn about that.
          Feel free to check in and provide updates, or contact me directly at mleach@downsyndromeprenataltesting.com if I can be of any help. I wish you the very best.–Mark

          • Just want to say thank you for all the helpful advice and information. I wish all parents who get the news that they are having a down syndrome child could be given lots of helpful and hopeful tips and info. as soon as possible instead of just being referred to a genetic counselor. I think awareness (in a positive light) and optimism are often missing from the conversation, and instead there is lots of worry, concern, and negativity associated with it. At least that’s been our experience this past month. So, your help was very much appreciated!

          • Thank you, Kristy–I’m glad I could be helpful, which was the whole reason I started this blog. When you feel comfortable, I hope you’ll share your experience with the study being conducted at Duke by some very compassionate genetic counselors seeking to identify ways to improve the prenatal experience. The study can be accessed at this link.

  30. Claudia Costabile says:

    I would really appreciate some perspective on what to think. My cffDNA came back with no risk for trissomies 18, 13 and 21, but a 2% chance of Turner’s. My genetic counselor thinks it might be a false positive since the ultrasound at 12 weeks looked normal. I’m having a second ultrasound at 16 weeks to check for signs before I decide on whether to do an amniocentesis, but the anxiety is huge, since we decided not to move on with the pregnancy in case we do have a baby with Turner.

    What does this 2% chance mean? I see other posts with 50% or more that turned out to be normal, but would the amniocentesis give me 100% chance that there is no Turner, or would the follow up ultrasound increase the certainty of this being a false positive? How are these percentages calculated?

    Also, the genetic counselor suggested the missing X cells could have come from my DNA, not the baby’s, so we are checking that, but I’m not sure what kind of certainty this would give me.

    Any advice you could offer would be greatly appreciated.

    • Only through diagnostic testing, e.g. a CVS or amnio, can you receive near 100% certainty for whether your child has a genetic condition or not. I’m not quite sure how an ultrasound would show anything one way or another, since I’m not familiar with Turner’s having such significant physical characteristics to appear at this stage of the pregnancy–I would consult with your MFM/OB on that. The professional organizations do not recognize the new blood test as being accurate enough for sex aneuploidies like Turner syndrome. At the same time, lab representatives have privately expressed qualms about testing for conditions like Turner syndrome since it has such a wide range of manifesting in the child, including to the point of almost being non-perceptible. I hope you will receive further genetic counseling and referral to Turner support resources to help with your decision.

  31. Colleen M says:

    Hi I took the maternity21 plus and now the genetic counselor says I’m positive for trisomy 13. She didnt say the % or odds. I’m of course freaking out and tomorrow is my CVS which I’ve been against and I never did it with my successful healthy triplets pregnancy 2 years ago. This pregnancy is a complete shock, we were told my many drs. we couldn’t conceive on our own. So now I wonder if my triplets could be affecting my current placental DNA testing?? Possibly causing the mosaicism… I’m 13 weeks so yet to see an u/s showing any abnormalties. I’m of course praying for my miracle baby to be 100% healthy like her triplet siblings. Any studies showing a false positive for a pregnancy after a multiples one?

    • Colleen–from a quick search of PubMed, I did find this article that found an association of high false positives for Down syndrome in pregnancies conceived via assisted reproductive technologies. Not exactly on point with your situation, but possibly informative. I would have your genetic counselor ask Sequenom what their clinical data is telling them. Coming up on 3 years since Sequenom launched its test, a situation like yours may have presented itself previously. If you do ask and Sequenom responds, please share.

      • Hi, I got all clear for trisomy 21/18/13 with harmony test. I also had the nuchal fold combined screening done and that gave me a 1:2 chance of T21. My Papp a was low and the nuchal fold was 2.7mm. I had an hour long scan done at the fetal medicine centre in London (professor Nicolaides centre ) and the dr couldn’t find any other markers from T21. She checked the cord, placental blood flow, nasal bone etc. I am unable to comprehend how one test could give me 1:10,000 result and the other test 1:2. Professor Nicolaides himself offered to scan me himself to recheck the initial scan but I am out of the country. My OB in Australia and the fetal medicine specialist don’t seem to trust the harmony results and say I need an amnio.. I am 40 by the way and just so disheartened by the varying odds, it’s ridiculous. Care to share any light?

        • Kavi–Ariosa, the maker of the Harmony test, has published research showing that their test is highly accurate after a first trimester ultrasound indicates Down syndrome. That research however was saying that where an ultrasound suggested Down syndrome, the Harmony test accurately identified each true case of Down syndrome. That does not mean, necessarily, that Harmony is equally accurate in ruling out those false-screen positive from ultrasound. However, NIPS is more accurate in ruling out pregnancies for not having a child with Down syndrome than it is accurate for detecting those pregnancies actually carrying a child with Down syndrome. So, the 1:10,000 result from Harmony would seem very reliable. Of course, though, the only way to know for certain is through an invasive diagnostic test. All of that said, you have a unique opportunity given your care by Dr. Nicolaides. Dr. Nicolaides was both a pioneer of nuchal translucency testing and he has consulted for Ariosa and published research on the Harmony test’s accuracy. I would suggest you ask him this question and I would hope you would share his answer.

          • Hi Mark, since my post I had another scan at 16 weeks and the baby looked good with no soft markers. Obviously 16 weeks isn’t 20 weeks so things may not still be seen but at the advise of Professor Nicolaides and the Professor here in Australia I saw we decided that was the best next move before an amnio. Had there been any markers on that 16 week scan I wouldn’t have hesitated to have the amnio. Obviously we will have the full anatomy scan at 20 weeks and praying that is all clear too. My obstetrician had just been at a conference for NIPT and explained to me that it is 99% effective in detecting T21, so I would be having the amnio based on being in that 1%, which we were not prepared to do with no markers. I assume if she had T18 & T13 something would have been showing up on the scans by now from what I have read.
            Unfortunately being back in Melbourne – my initial testing was done in London under Professor Nicolaides clinic, I no longer have direct access to him, but am lucky to be looked after by one of his students from many years ago who remains in contact with Nicolaides. I will be sure to update with 20 week scan details.
            Hope this helps someone.

          • Thank you for the update. I wish you the best as your pregnancy continues.

  32. Amelyn Foo says:

    Hi. I got a “positive” screen result for Down syndrome based on the blood sample taken, even though the nuchal translucency measurement was 1.1mm. I am 35. We did the Harmony NIPS test about 2 weeks ago and it indicated that we were in the clear for Downs, but instead was high risk for Turner’s Syndrome or Monosomy X.

    As you can imagine, it has been a helluva fortnight. Each test we took, brought something new to worry about. We got an amniocentesis done yesterday, and the preliminary Fish test result was that they found the second X chromosome and no Down syndrome. All I can say is, I hope that they don’t come back with something else to worry about with the final results.

    Just wanted to share my experience and my understanding of the Harmony NIPS.

    1. Harmony NIPS tests placental DNA not fetal DNA, so the sample is not the best sample.
    2. Harmony NIPS is a reasonably good test for Down Syndrome, but not necessarily the other chromosomal conditions. They say that there is a risk, (99% even) but they have been known to have been WRONG!

    So, dear ladies / future parents, take heart and don’t lose hope.

    Thanks for the post, Mark Leach. I found it helpful.

    Kind Regards,
    Am

  33. Hi! I am 26 years old, my husband is 32. And I am at my 12 weeks pregnancy with my second child. Today, I was at the doctor’s office-for the first trimester screening, the ultrasound shows that the baby is perfect, however, by the blood levels: I am the high risk group for Trisomy18. They took my blood for Cff DNa screening, and have to call me next week. I am so nervous. Can somebody tell me please how accurate the regular blood screening is? And my doctor said that CFFDNA is accurate for 99%.

    • Traditional screening tests have between a 2-5% false positive rate. CfDNA tests are more accurate, but still have false negatives & false positives, particularly with rarer conditions like T18. Other posts on the blog explain further. Feel free to share your results & I hope you receive the counseling & support needed throughout your pregnancy.

  34. Hi, I’m 12 weeks pregnant and took the Panorama test 2 weeks ago. My doctor called me on Thursday and said my baby is at high risk for down syndrome, the percentage is 70%. I am 29 years old and will be 30 at delivery. How accurate is the Panorama test? Are the chances of my baby carrying DS really 70% or can they be lower? How do they calculate such percentage? I found your article to be the only one giving chances of false positives. We have an appointment on Thursday with a specialist. But I’d appreciate your opinion. Thank you in advance.
    Susy

    • Susy–Taking your questions in order: How accurate is the Panorama test? No one knows. And that applies to all of the NIPS tests. This is because their stated accuracy is based on clinical trials of small populations (relatively) that have a higher than natural incidence for Down syndrome. Are your chances lower than 70%? More than likely yes. Even if the accuracy was at the stated 99+%, based on your age, that means you really only have about a 50/50 chance of having a child with Down syndrome–meaning you have just as much of a chance of having a child without Down syndrome as you do with Down syndrome. How do they calculate such percentage? I would ask your doctor, because typically the NIPS labs do not report the positive predictive value, meaning how likely it actually is that you are carrying a child with Down syndrome. To see how you have a 50% chance based on your age with a screen-positive result, see this post here. I would ask to see a genetic counselor if you haven’t already been referred to one. If you would like to learn more about Down syndrome, please see the Resources tab on this blog at this link.

      • Thank you for replying. I have an appointment on Wednesday with a genetic counselor, but the waiting is terrible. I read a lot about the Panorama test and they state that their results are the most accurate ones in the market and their accurancy was also tested on low risk population with the same results. They even provide you with personalized percentage. Mine is 70%. They really don’t give much hope for false positives.
        Either way we are keeping this baby, but just debating wether or not to also have the amnio test done or to just tell my doctor to treat this pregnancy as a down syndrome one.
        Thank you again.

        • Susy–many women are making the decision of relying just on the NIPS result and as a result the number of amnios is plummeting–it’s something that is reported at every medical conference since 2012. If you do plan on continuing, then I would recommend you reviewing “Diagnosis to Delivery.” The book is available for free on-line as a .pdf and was written by moms who have supported those continuing after a prenatal test for Down syndrome. If you do read it, I hope you find it helpful.

    • Susy, my blood test (in July) came back 99% positive for Tri 21. An amnio confirmed it. We wanted to know for sure so we could prepare. I know of no one like me who is currently carrying and planning for a DS baby. From my research and all the people I’ve talked with, it’s not as bad as we are often led to believe. The parents I’ve met of DS children absolutely love their child, and so many have said it has been a blessing. It’s been a bit of an emotional roller coaster as we’ve let the reality sink in, but we are really excited to meet our little guy and know we will have many positive experiences ahead. Yes it will be hard, but we will have precious experiences often. And, so many resources are available these days to give help and support! Best wishes to you!

      • On-line support for expectant moms continuing their pregnancies can be found at the babycenter Down syndrome pregnancy board. The Down Syndrome Diagnosis Network supports new and expectant parents. You can access DSDN via its website or its Facebook page.

        • Just an update. Today we went for the NT scan and at 12 weeks and 3 days the measurement was 2.8 mm. They told me that it is higher than normal so they assume the Panorama test is a true positive. Still struggling accepting the new reality. Still feeling scared.

          • Anxiety is an effect rarely discussed when counseled about prenatal testing. I hope that if you think it helpful you’ll find the on-line resources mentioned previously helpful in dealing with the stress.

          • I found that website very helpful. Thank you Mark.

          • Susy, I’d be happy to email back and forth, but don’t want to leave my email address on such a public site (maybe Mark could share it with you if possible, since we have to leave our email address to comment, but it’s not public…..). I am very aware of all the feelings you are going through, I went through it all myself. It’s all I could think about. It consumed everything. I was very worried and had a roller-coaster of emotions. I think it’s a shame honestly that they test for it so early (in your case). It can cause so much unnecessary anxiety and stress! And, I think testing positive for Tri 21 is viewed as such an awful diagnosis and, yes it’s scary but not the end of the world. I am at peace about it now and just want our little guy to be as healthy as possible and have as happy a life as possible. I’d be so happy to talk with you/email you…! Oh, and my cousin and others I know have been through the same thing, but then it was confirmed that they were NOT carrying a baby with Tri 21. So, it could still all be okay and your baby could turn out normal. For me, I’ve met too many parents who ADORE their child with DS and say it’s been such a blessing, etc……that I can’t get too down about it. We’ve had an outpouring of love from our community which has been helpful as well. Just know that I know what you are going through. It’ll all be okay! :)

  35. Hi Kristy,
    Thank you for replying. Since the test came back positive I haven’t done anything else but crying. I originally took the test just to find out early about the gender of our baby and the positive result was so unexpected.
    I’ve read so many wonderful experiences of parents with down syndrome kids and that gives me hope, but I’m still so scared. Tomorrow We have an appointment with a genetic counselor. I still don’t know if I should do the amnio or not. I’m only 12 weeks pregnant so I will have to wait 3 more weeks for it. Nobody better than you can understand our feelings. Either way I do believe that once the baby is born everything will look different and for the better. I wish all the best to you and your baby. Every baby is a blessing from God! We just have to be strong!
    Best wishes

    • Juliette S. says:

      Hi Suzy,
      I just had the first trimester screening by Verfi and got the dreaded phone call today that the baby most likely has DS! I am terrified and confused! We have an appointment for CVS testing on Thursday, but can’t stop crying! Feeling alone and scared! Praying for a false positive, but also expecting the worst! :( reding these blogs have helped me and I just wanted to reach out to you!

      • Juliette–thank you for your compliment; I’m glad the posts have helped. Given your name, if you search on the blog for “Juliet,” you’ll find photos of my daughter, who happens to have Down syndrome. I would also point you to this post where you can find out what a “positive” Verifi test really means for you chances of having a child based on your age (e.g. if you’re under 30, you have less than a 50/50 chance). If confirmed or if you choose not to have diagnostic testing and still would like to learn more about Down syndrome, please check out the prenatal resources tab.

      • Hello Juliette,
        I perfectly know how you are feeling right now. When I received the call it really felt like the end of the world for me. A month later things look a little different. I am finally starting getting excited about this pregnancy again. I am still so scared about our baby’s health. We still don’t know if she’ll have health problems. We have our next ultrasound in two weeks and they’ll probably be able to check her heart and let us know what to expect. We opted out for the CVS or amnio. At our last ultrasound they said that the NT scan was higher than normal 2.7 mm so that pretty much confirmed the positive Panorama result. Right now I am 16 weeks pregnant so I still have a long way to go. How far along are you? What helped me the most was reading the wonderful experiences of families with down syndrome kids have to share. Mark suggested us to check the Down Syndrome pregnancy board. I read it everyday and left a message when needed help… Or Hope! Those moms are so supportive and they understand what we are going through. If you want to keep in touch we can ask Mark to share our emails in private so we can support each other during our pregnancies. Hugs to you.

  36. I’d love to e-mail you too. Hopefully Mark will be able to provide you with my e-mail or vice versa. You described exactly how we are feeling now. It’s been such a shock for us and I do regret taking that test. It’s been 8 days and I still feel so miserable, but I need to find the strenght to face it and react! Well I hope to hear from you soon! Thank you for your message… It helps knowing there are so many people in the same situation. Hugs

  37. Hi Mark,

    Recently, I just received feedback from my insurance underwriter that request me to do amnio test although i already submitted my Harmony Test that shown low risk of Ds 0.01%.

    What I confuse which test is more accurate. Per my understanding from my gynae, the harmony test is more accurate than amnio test, and risky to fetus.

    Pls help to advise.

    Thanks.
    YS

    • I’m concerned that your medical professional believes Harmony is more accurate than an amnio. It is not. Amnio (or CVS in the first trimester) are the only diagnostic tests, but they are invasive and therefore do have a risk of miscarriage. Harmony and others like it (MaterniT21, Panorama, verifi) all have false positives and false negatives. That said, the accuracy for ruling out pregnancies carrying a child with Down syndrome is very high for Harmony and others like it. Many women are relying on the Harmony result if it is a screen-negative rather than risk miscarrying from an amnio.

  38. Hi Mark, I have read this article and the plethora of comments below with a lot of interest. It is the first place I have found that takes a frank and honest view at the various NIPT tests and doesn’t have any bias. I am currently 11+6 weeks, have my NT scan this Friday (NHS) and have also got a Panorama booked for two weeks time and an Amnio for 6 weeks time (both arranged privately). Some have shown surprise at us booking the Amnio so soon without any indicators of anything to worry about and it is not due to the fact we suspect we have issues (no family history and ages 31 & 34) but more due to wanting to be sure as we would take action if we discovered our baby had any chromosomal anomalies. The thing is we decided before we even tried for a baby that we wanted an Amnio but have since been researching the screening accuracies of the NT and the Panorama.Having read your comments on here it seems there are still a lot of issues with the accuracy of the Panorama in particular the fact that it checks placental not fetal DNA – which i didn’t realise until reading your article. As our screening results will be back a week or so before our Amnio we have the ability to make an informed decision but I would dearly love to avoid the Amnio due to the risks and discomfort. I wanted to find out if anyone else on here has had the same dilemma and what they decided to do?

    • I hope others will respond. As I have mentioned in other replies, more and more women are opting to rely on a screen-negative result from tests like Panorama as their false negatives are very low. So, if they receive a screen-negative, they are choosing to accept the slight risk of a false negative versus the higher risk of a miscarriage from an invasive test, like an amnio.

  39. I commented here back in February after a Panorama test came back 73% positive for Turner Syndrome (Monosomy X). We opted not to have the more invasive yet definitive tests like an amnio since we decided termination would not be an option, but we did have monthly ultrasounds with specialists at a renowned children’s hospital. Every ultrasound was deemed “textbook” and even “A+” by doctors. Our daughter had no physical signs of TS. We were then hopeful that the NIPT was a false positive or that I had placental mosaicism. In August our daughter was born and again she was examined and found to be in excellent physical condition. However, when cord blood tests were conducted it was determined that she has Mosaic Turner Syndrome-some of her cells are missing an X and some are not. I did go through some grief because it’s probable that she will be infertile and may face a few other issues. However, I’m glad that that I know now. We have already met with some TS endocrinologists and together with our pediatrician we are able to monitor my daughter’s progress. I’m so thankful that I read your articles, Mark, because it really helped me to understand what an NIPT is looking at. I truly feel like there needs to be better and more resources to be able to help people know what these tests are and how to handle results. I’m not going to weigh in on parents deciding to terminate except to say this, an NIPT should not be the sole basis on which parents decide to terminate since it’s not the same as tests like an Amnio. Secondly, in the case of TS and especially mosaic TS, these girls have very normal lives. It makes me sad when I read online how many people opt to terminate after a test knowing little to nothing about what TS is or being misinformed. I feel like NIPT’s are a little like opening Pandora’s Box. More needs to be done to help parents with the results they receive. Thank you, again, for your help Mark in helping me to be properly educated about these tests after I initially received my results. I hope others will continue to find this site and read up. :)

    • Laura–Congratulations on the birth of your daughter! And you’re right about parents not making a decision to terminate based just on a NIPS result–even the test laboratories agree that confirmation should be had by diagnostic testing. Thank you for your kind words–makes it all worth it.

Trackbacks

  1. [...] blood stream. Note the removal of “fetal” from the traditional acronym of cffDNA. As I wrote previously, this is because most of the DNA tested is not, in fact, from the fetus. ACMG makes this point, [...]

  2. [...] and Natera–have entered the market. NIPS uses samples of the mothers blood to identify cell-free DNA to assess the likelihood of the fetus having Down syndrome. Originally promised to be diagnostic, [...]

  3. […] good (same with the NT ultrasound) & we're having a girl These are 2 helpful things I found: http://www.downsyndromeprenataltesti…etal-dna-isnt/ […]

  4. […] tests results can predict a patient’s outcome. One needs only to review the comments at this post to see the confusion caused by how NIPS labs report their results to […]

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