At the beginning of February, the Society for Maternal-Fetal Medicine held its annual conference. Again it was reported that the new non-invasive prenatal test is inferior to traditional screening because it misses too many conditions.
Mary Norton, an physician at the University of California, San Francisco, has served in a paid capacity as an advisor to NIPS laboratories Ariosa, maker of Harmony, and Natera, maker of Panorama. Which is why her recent research is all the more telling.
From Caroline Helwick’s article in Medscape:
Cell-free (cf)DNA analysis appears to be less effective as a primary test to detect fetal chromosomal abnormalities than sequential screening, new research has shown.
Norton led a team of researchers comparing how effective NIPS was at detecting chromosomal conditions versus traditional sequential screening.
NIPS has been covered extensively on this blog, but basically, it tests placental DNA for a limited number of aneuploidies, conditions like Down syndrome and Trisomy 18, and has been marketed as testing other chromosomal conditions caused by micro deletions, like DiGeorge syndrome (though no professional organization recognizes any NIPS test for these non-aneuploidy conditions).
Sequential screening is a two-step process involving traditional screening. First trimester screening, called the “combined screen,” involves an ultrasound measurement of the nuchal fold at the back of the fetus’ neck–called nuchal translucency or NT–and a test of the mother’s blood for certain markers. Then, a second trimester screen is performed using the long-time screening test called the “quad screen” which tests for four markers in the mother’s blood. These first and second trimester screens are then analyzed together to report a recalculation of the mother’s chance for having a child with a number of chromosomal conditions.
Now, recall, that NIPS has been marketed as “Clear. Compelling. Convenient.” by Sequenom, and called the Holy Grail by practitioners for its accuracy. Norton’s research, however, shows that instead NIPS is not as clear, compelling, or convenient and the cup of the Holy Grail is smaller than the pool of genetic conditions detected by sequential screening.
From the Medscape report:
In the cohort of 452,901 women, 74% were younger than 35 years of age. Abnormal karyotypes, detected in 2575 women, were less likely to be identified with cfDNA than with sequential screening (75.4% vs 81.6%).
(emphasis mine). The results are illustrated in the table from the report:
As the table shows, NIPS (cfDNA) has a higher percentage detection for aneuploidies, but detects none of the other conditions identified by Sequential Screening.
(It should also not be overlooked the relative accuracy NIPS has for each aneuploidy. NIPS is advertised and commonly misunderstood as having “99% accuracy,” but based on this study, NIPS only detected the following percentage of each aneuploidy: Trisomy 21 (99%); Trisomy 18 (97%); Trisomy 13 (92%); and sex aneuploidies (85%), for a combined accuracy rate of 96% NOT 99%. Still relatively accurate, but not as accurate as the NIPS labs tell patients and providers).
Perhaps most telling about this study is how NIPS is not providing the vaunted reassurance it claims to provide.
Most women accepting prenatal testing are doing so not because they expect to have a positive result for a genetic condition. Instead, they rightly expect they are in the vast majority of women who are not carrying a child with a genetic condition. They are seeking reassurance. But, according to this study, NIPS potentially has a higher false negative rate than traditional screening.
This means women receiving a NIPS screen negative result, i.e. a result saying no genetic conditions were detected, could be less accurate than with sequential screening. To make this point more clearly, you see that last number in the table above labeled “Other.” Those are 560 moms who had a child with a genetic condition and NIPS would tell all of them, “Nope. Your child doesn’t have a genetic condition according to our test.”
What’s still missing from NIPS
I began this post by saying “Again” it was reported that NIPS was inferior to traditional screening. That “again” is because at the previous year’s SMFM conference in 2014 it was reported by several studies that NIPS failed to identify as many conditions as other variations of prenatal testing.
Norton’s latest research reported at the 2015 SMFM conference again shows that NIPS is a limited test, does not have the level of accuracy that NIPS laboratories advertise, and does not detect as many conditions as traditional screening.
Thanks for the article, Mark.
Now I’m a bit concerned. I am 16w3d and I’ve had the Panorama test (at 10w3d) and it came back low risk. I am and will be 34 years old at time of delivery of my first child in my first pregnancy.
On Friday, at 16w, the doctor drew blood for AFP test. I am in California, so I’m not sure if they only test AFP or if – by law – they test more.
However, those are the only 2 official tests I’ve had (the AFP results are pending). My OB did not do a NT scan, but I went separately to a boutique sonogram place and the tech measured the NT (at 11w1d and again at 13w1d) and said it was thin @ 1 something, I don’t remember exactly what, but she said the baby “looked good”. She also added that the femur length looked normal. The reason my OB didn’t do NT is because he said he didn’t do that anymore because he did Panorama now.
I am scheduled for my anatomy scan on 3/12, when I will be 18w6d.
Also, my husband and I did pre-conception genetic testing through Counsyl, where they tested 102 different conditions, I was positive for 2, but he was negative for all.
I’m worried I haven’t had all the possible screening I could have had.
I’m trying to avoid an amnio as much as possible.
Is there more non-invasive screening I can do at this stage of my pregnancy?
Thanks
Ali–it sounds as though you’ve done about as much as you can do to provide you the reassurance you may be seeking. I’m surprised you were offered Panorama since your age doesn’t make you AMA yet and NIPS is not recommended for low-risk populations. That said, with a screen negative result, those are more reliable than a screen positive, i.e. the chance of a false negative is exceedingly low–so low that many women are relying on a negative NIPS result and foregoing the risk of a CVS or an amnio for the certainty those tests can provide. The only thing I can think is if you had blood drawn in your first trimester, they could still test that as though it was the first trimester combined test, and then incorporate those results with your AFP/quad results to give you a sequential score. Something to ask about maybe? Also, NIPS can be done throughout the pregnancy and is actually more accurate the further along it is done in the pregnancy (reason being more time for cfDNA to enter the mother’s blood stream). Having already received a Panorama screen negative, another NIPS test is not indicated and likely won’t be covered, but if you’re willing to pay out of pocket, Ariosa’s Harmony test could be done for around $800. It’s testing methodology is different than Panorama’s, so perhaps if you got a screen negative from Harmony then that would be two NIPS screen negatives and enough for your comfort level. But, be aware that accepting any testing can return results you don’t expect and that should be weighed as well in your decision.
Thank you for the info, Mark. I will look into the Harmony test. I’m wondering though, I hear a lot about 35 being the sort of big *threshold* age. I am 34, is there any science that backs up that there is a BIG difference between 34 and 35? I have constantly considered myself more 35, than say 25, despite the fact that 34 and 25 are both not considered AMA. I just think that my egg quality is much closer to the 35 year-olds than younger moms than me.
Ali–well “big,” is a relative term and subjective (I attended a dinner Sunday with some outdoorsmen; it seemed all of them had caught a “big” fish). That said, see this post here which has the chart showing the increase in baseline chance for having a child with Down syndrome based on age. To see the information in a different way, see the chart at this post, which shows the chance that a woman is NOT going to have a child with Down syndrome, decreases from 99.89% as a 30-year old to 99.7% as a 35-year old. If you don’t think an 0.11% decrease is “BIG” from 30 to 35, then the difference between a 34 and 35 year old would be marginal. Hope this helps.
thank you for your post mark. i am 41 and my pregnancy was thru ivf. they transferred 2 frozen embryos and only 1 implanted. i had two small spotting during implantation time. or was it vanishing twin/embryo? my hcg before my ultra sound was high in the twins level. until they found one heart beat at week 5, hcg became normal. my ivf clinic was concern at first with over 1050 hcg at 4 weeks, baby should have heart beat. since baby was ok, i was released to my obgyn and they mentioned i had a small hemotoma by the embryo. in the beginning of my 1st trimester, all was fine but then i started spotting many days. the hospital found the small hematoma near the embryo as well. at my 1st trimester screening, they found that baby had a thick NT of 3mm to 3.7mm and was concern with down syndrome. i took the verifi nipt test that same day and the results came back screening positive 95% for T21. my heart was shattered and it still hurts. i just had my amniocentesis yesterday and i came across this article. it appears many people in the comments experienced a false positive. i also want to mention that since then, at my amnio, the baby’s thick NT went away. he has a nasal bone. and they found no markers for anything. baby even has all his toes. dear mark. what do you think of my chances for a false positive? do you think my past fail ivf transfers can mess up my blood. we also did transfer two embryos this time. the one that did not make it, was it possible absorbed into my blood? i read articles by a dr sher that most women from ivf where multiple embryos are transferred experience early vanish twin/embryo before they have their ultrasounds that they never knew they had a vanishing twin. or can the failed embryo be absorbed into the current baby’s placenta and caused the nipt to pick up the extra dna? i also read articles that even during sperm stages, sperms gave dna already. embryos have their dnas as well. can the failed embryos from ivf have messed up my blood causing the positive t21. can by current baby at 16 weeks a normal baby? as some articles say, babies with down syndrome don’t make it past 1st trimester. do you feel he has a chance to be normal and live a normal life? i’m just so worried. and stressed every minute, every day for the last 2 weeks. pls advise. thank you so much.
i forgot to mention, i took a carrier test as well and all came back negative. but doubt that helps with the baby’s situation.
If this were a singleton pregnancy, the PPV calculator calculates your chance of it being a true positive as being 95% (like verifi reported), with a 5% chance of a false positive. Tests like verifi take precedence over the presence or absence of soft markers on ultrasound. However, because more than one embryo was transferred, that may affect the accuracy. The amnio result will be diagnostic. You should have been provided information about Down syndrome; if you were not, here is the link to the recommended resource.
Thank you so much for your detailed insight on the NIPS. I really wish I had found your site and the information 10 weeks ago so I would have been more informed.
I am 42 years old and 20 weeks along with a big surprise 2nd pregnancy. Upon recommendation of my OB I had the Verify test right at the 10 week mark. The results came back negative with no aneuploidy detected for 21, 18, 13,9, and 16. I was assured by my OB there was no need to do any further testing. No need for CVS, no need for the quad screening and no need for an amnio. All is well and as he reported “your baby girl is health”. What I did not realize at the time is NIPS is really just a screening tool unlike the CVS I had with our first child at age 37. CVS was explained so thoroughly and all options were given pending the results. None of that info was included with NIPS. None of it. I should have followed my gut instinct.
Fast forward to today’s 20 week ultrasound which included lots of measurements. The MD came in the room after the tech finished to do a few more measurements. My heart sank and I nearly passed out. I knew what had to be coming, a Downs diagnosis, despite a negative NIPS 10 weeks earlier that was supposed to put us all at ease and our baby in the clear. The abnormality noted is an intracardiac echogenic focus. A what ? I asked. The MD went on to explain this was a normal variant because my NIPS was negative and she would recommend an amniocentesis if I did not already have the negative NIPS. An hour later the same info was reiterated by my OB as he moved right through my 5 minute appointment. At no time was an amnio offered or discussed. I am confused, and even more I am angry. I am angry the Verify NIPS has been portrayed to me, and I know many others in my mom’s circle, as being 99% accurate. I know false negatives are rare, but I do believe I had rather have a false positive to rule out via a diagnostic test than a false negative no one seems to consider may be of concern.
Based upon your understanding and depth of info with the NIPS and communication with others who have had myriad of tests, what are the false negative numbers? Is an amnio warranted?
Thank you
Dawn–Professional guidelines advise that NIPS results, like verifi, remain screening tests and certainty can only be provided by diagnostic testing. Further, the NSGC’s fact sheet on NIPS explains that because CVS tests the same genetic materials as NIPS, it is not as confirmatory of a diagnostic test as amniocentesis. That said, if I’ve done my Bayesian analysis correctly (which you can read about at this post), your chance of having a false negative, given your age, is 0.005% or roughly 1-in-20,000 [however, I’m a lawyer, and the joke is we go to law school because we’re not good at math; I would have what is called your “negative predictive value” confirmed by a genetic counselor or medical geneticist]. All this being said, an amnio remains the only diagnostic test to give the best certainty. However, since you have a screen-negative NIPS result, I don’t know if that would be covered by your insurance, so you may be going out-of-pocket to pay for it. If that is the case, I would consider running another NIPS test. Again, something that won’t likely be covered, but that may give you the certainty you desire since the chance of two false negatives would be even rarer. Plus, as the pregnancy progresses, there is more cell free DNA from the pregnancy in your bloodstream to be tested providing more accurate results. Finally, as this post covers, though, there remain conditions that NIPS cannot test for. If you had other traditional screening (NT or quad), I would consider those results as well and determine whether you should undergo an amnio.
Thank you for your detailed response. We have spoken with the OB and the MD who interpreted the U/S findings. Both do not recommend an amnio as they say the risk of amnio complications outweighs the odds of the baby having a trisomy 21. I am concerned with their hesitancy with a miscarriage rate of 1/600 or less.
Monday we will speak with the genetic counselor as you have recommended. My largest concern is the Verify test having been conducted at 9 weeks 7 days gestation and that the fetal fraction was too low to provide accurate negative results.
Lastly, we did not have other traditional screenings as you mention (NT or Quad). Apparently our OB is of the belief that the new NIPS are the best and most accurate thing and a negative result is ‘the gospel’.
Thank you again.
I hope you get more accurate advice from your GC (and have him or her check my math on your NPV).
Hi Mark – I will be 38 years old at the estimated time of delivery of my 2nd child. I had the Panorama test when I was 12wk6d pregnant. My results were low risk for everything except Trisomy 21. Here are my specific results: Age-based Risk Score: 0.85%, Risk Score: >99%, Age-based Risk Text: 1/117 (0.85%), Risk Score Text: >99/100 (>99%), Age-based Risk Fraction: 1/117, Risk Score Fraction: >99/100, Result Text: high risk. Fetal Fraction: 12.7% Based on this information, my doctor said there was really no need to proceed with an amnio as the Panorama results were indicating a 99% chance of Down Syndrome – and that the amnio would only just give us that extra 1% of confirmation. (Really?). I have read a number of posts about false positives and the importance of PPV and the limitations of NIPT (NIPS) – but I am so confused as to how to apply that information to my results. Can you even attempt to clarify what these results really mean?
Holley–the age-based risk score is correct: that as a 38 year old mom at time of delivery, your baseline chance for having a child with Down syndrome would be 1-in-117 or 0.85%. However, the “Risk score” of greater than 99% I can’t accurately interpret. I expect that Natera (the maker of Panorama) is simply repeating its claimed accuracy for detecting pregnancies carrying a child with Down syndrome with greater than 99% accuracy. However, based on your baseline chance form your age, even with a greater than 99% detection rate, you would still have a greater than 10% chance of receiving a false positive. (This is explained at these posts here and here). If your doctor is advising that an amnio would only provide 1% more certainty, that is incorrect. It is the only test that provides any certainty, because Panorama remains a screening test with false positives and false negatives. If you intend to continue your pregnancy, then it is appropriate to counsel on whether the certainty gained from an amnio is worth the risk of miscarriage. However, if your doctor is counseling patients who are considering termination as an option (and I’m not presuming whether you are in that group of patients), then he or she is committing malpractice. Every professional guideline emphasizes that results like Panorama should be confirmed with diagnostic testing prior to making “irrevocable decisions,” i.e. terminating. One final question for you: the National Center where I serve at provided Natera with 2,000 free copies of Lettercase’s “Understanding a Down syndrome diagnosis,” the recommended resource for women receiving a screen-positive result, for Natera to deliver to their provider network. Did your doctor provide you with a copy? If not, I wonder whether he or she ever received a copy from Natera? I hope this has been helpful.
If you have been helped by the information shared here or elsewhere on the blog, then in honor of World Down Syndrome Day (March 21), I hope you will support the National Center either through taking advantage of Lettercase’s sale or with a donation. More here at this post.
Hi Mark, I had my anatomy scan on friday May 8th at that time we went over both my blood tests again..the 1st was the cell free dna which came back negative than we went over my quad screen test which came back positive for down syndrome. She told me that the cell free dna out weighs the quad screen and I have nothing to worry about..with the cell free being down at 12 weeks and the quad screen done at 17 weeks I am now very concerned and have been thinking about having the amniocentesis test done this friday when I go back.. (the baby would move off of his back to get scans of his spine) would you recommend the amniocentesis test with both tests coming back with different results. I am 34 will have turned 35 4 days before my due date…this is my 2nd child l, 13 years apart. Thank you Jolene
Jolene–what you were told is correct. The quad test, the second trimester blood test, has much higher false positives than cell free DNA tests have false negatives. Many women are choosing to rely on the low chance of a false negative from a cell free DNA test in order to avoid the higher chance of miscarriage associated with diagnostic testing. That said, the phrase, “you have nothing to worry about” is a bit overstated. Cell free DNA tests still do have false negatives, though very rare. From the start, be it quad testing or cell free DNA, the only way to know for certain prenatally is with an amnio. I am not recommending any test one way or another because that would fundamentally turn on what ultimately you want to do with your pregnancy and with the information provided by prenatal testing. But before any irrevocable decision is made, then I would recommend an amnio so that you know for certain whether your child has a genetic condition. If, however, you’re seeking reassurance and not wanting to risk a miscarriage but are willing to accept the relatively low chance of a false negative, then I would rely on the cell free DNA test knowing that there is a small chance of a surprise at birth.
Thank you Mark for your quick reply and putting my mind at ease. It was just very alarming to get one test that is negative than find out weeks later another test returns postive, she also stated that the quad screen is testing my blood and proteins and not the babies which makes the cfDNA more reliable and pretty much cancels out the quad screen…I guess I was just worried with the quad screening done later and maybe there was a change. Thank you for your insight Mark.
Jolene
Depending on how much it’s worth it to you, you could do another cfDNA test, though I doubt it would be covered by insurance. However, the later in the pregnancy, the more cfDNA is in your bloodstream, and, ergo, the more accurate the cfDNA test. If it came back screen-negative again, then that would be incredibly unlikely to be a false negative.
Thank you, I think I will look into that! I really appreciate all of your help
Mark, is there any scientific evidence the labs report on for whether a result would be rendered if the fetus had passed at the time of the blood draw? After getting a cfDNA test without a recent scan, I wondered if the possibility of a missed miscarriage could have occurred and whether I’d still get results from the blood or if they would somehow know. I looked all over for someone who might have an answer to this, and figured with all your insight you might.
Cell free DNA floats in a mothers blood from her current pregnancy and all of her previous pregnancies. Therefore, if you had a miscarriage before, there is a chance the test sample tested that cell free DNA. Further, when the tests initially entered the market, even the labs noted that the phenomena of a vanishing twin, where there was another embryo that did not develop, could produce the cell free DNA that results in a false positive. I would discuss these concerns with a genetic counselor or maternal fetal medicine specialist, if you haven’t already.
Mark,
Thank you for your detailed writings and focus in this area. I am 5weeks and 2 days pregnant and I am beyond stressed over the idea that my child could have some sort of defect. If costs was not an issue, what prenatal screens would you recommend and at what intervals? I feel like there is so much conflicting information on the web. I am overwhelmed and would appreciate your guidance on NIPGS.
Thank you,
Lacey
Lacey, congratulations on your pregnancy and I’m glad you’ve found what I’ve written here of some use. The only way to know for certain whether your child has a genetic condition is through diagnostic testing, the most accurate of which with the least amount of risk of miscarriage is an amniocentesis. I have written in a separate post how having cell free DNA screening (cfDNA AKA NIPGS) can be justified before having an amnio since it has very low false negatives, so low that increasingly more women are relying on a negative cfDNA screen result. While there remains a slight chance of a false negative, expectant moms are willing to accept that risk in lieu of exposing their pregnancy to the risk of miscarriage from an amnio. So, you could have a cfDNA screen, preferably at the beginning of the second trimester since the amount of cfDNA increases as the pregnancy progresses, and, then, you could decide after receiving the results whether to confirm with an amnio. Note, though, that this is just for genetic conditions, and as this post covers, cfDNA screening does not identify all genetic conditions. There remain the structural conditions like spina bifida that can be screened for with AFP screening and a second trimester anatomical ultrasound scan, which should be done regardless to identify any physical complications. I hope this helps.
Thanks for the article. It would be busy time for you. But, I need any feedback.
My wife had n ultrasound at 12 w +5 days. Before the test, we got a result from the harmony test showing low risk. It was our first baby so that we spent extra money for more accurate one.
While having the ultrasound, the doctor mentioned that our baby has the increased neck thickness. It is – 3.6mm.
We wanted to measure it again. However, it was not possible due to the holidays. Moreover, our OB told us that even if we get the better result in the second or third NT test, the 3.6mm cannot be denied.
Now, she suggested us having the amnio. Bacause of the risk of the invasive test, we haven’t decided it yet. We need to answer whether we will go for the amnio or not by next wendseday.
What do you think? So far, expdct for the NT size of 3.6mm there haven’t been any markers.
Please it would be appreciated if you can reply. Thank you 🙂
Both the NT and the Harmony are screening tests, so neither reports definitive results. From the beginning the only way to know for sure is with an amnio. That said, the rates of false positives are much higher for the NT screen than for Harmony. Similarly, the chance of a false negative with Harmony is exceedingly low. But, if you want to know for sure either having an amnio or finding out at birth are the two ways. Amnios are not to be performed before week 15. Given that you would have some time before then, you could request a second ultrasound screen and see if the NT had lowered. If it had, that plus the Harmony may make you decide to avoid the risk of amnio. Also, you could always seek a second opinion or have another practice do the second ultrasound. I hope you find the information you need to make your decision.
I had a question regarding the specificity of determining the fetal sex. Since the NIPT tests (I’m assuming they are all the same in what they are supposed to detect) use maternal blood, and don’t actually get fetal blood, is it possible for the fetal sex prediction to be incorrect? I have read multiple posts about women told they were having a boy to find out at their anatomy scan, and at birth, that they were and had a healthy girl. Apparently women can have ‘y flags’ or other chromosomal dna in maternal blood can be confused for the Y chromosome? I have heard of this more than predicting girl and being told boy later. Do you have any insight on this? I have read that the 99% accuracy for fetal sex is not actually accurate at all. Thank you
Janelle–the professional guidelines recognize cell free DNA (cfDNA)screening as able to detect sex with sufficient reliability to be used as a screen. A screen, however, has false positives and false negatives as you have read about yourself. I have not seen a study that has analyzed whether cfDNA screening reports results for sex with a 99% positive predictive value (PPV), i.e. that a report of “male” means the mother has a 99% chance of having a boy. I know of many other studies, however, that show how a cfDNA screen result for one of the chromosomal conditions it screens for does not report a 99% PPV. You could have your provider contact the lab to ask what your results’ PPV is for sex and I’d be curious what the lab would say.
Mark,
I posted previously. We had the harmony test and got a probability of 33% for triple x. Our daughter had cord blood karyotyping done and those results today came back as normal. No triple x. This is a huge relief however the doctor said there was a chance of error (maternal cells) and he offered to do another blood test on our baby.
I so sick of tests and waiting on results at this stage. Do you know how reliable the cord blood test is? Is this something that is used to confirm other chromosome syndromes post natally? I cant understand why they wouldnt just have taken blood directly from the baby at birth in this case?
Appreciate any thoughts or information on this,
Unfortunately, I can only echo your same wonderment at why they didn’t just take blood from your baby?
Hi Mark,
I’m 33 years old and pregnant with my 3rd child. My first 2 children are healthy. During the first trimester ultrasound at 13 weeks and 2 days, the nuchal translucency was measuring over 4mm. My OB didn’t give us an exact number. He read the report given to him. That same day, I had my blood drawn in order to complete a panarama. Today, at 14 weeks and 3 days, the OB’s office call and said the results came back as low risk. My husband and I are so confused. We would like to move forward with an amniocentesis but sure if that is necessary given the low risk panarama report. Any thoughts on our situation? Thank you!
A nuchal measurement alone is not the recognized screening protocol for Down syndrome; it’s to be combined with a test of your blood (not like Panorama, this test tests other info in your blood). So, an increased nuchal alone is not recognized as indicating Down syndrome. Your Panorama result, on the other hand, provides you a negative predictive value, i.e. the chance that you child does not have Down syndrome, at greater than 99%. You can find this calculation by plugging in your age at this NPV calculator. From the beginning only amnio can provide you with certain information, but many women are relying on the high NPV of a cell free DNA screen like Panorama to avoid the risk of miscarriage associated with amnio.
Hi Mark. Does the gestational age effect these tests? The further along one is the less accurate it is? Or no correlation?
The further along the more cfDNA there is to test and therefore studies find the accuracy increases.
Hello Mark: At my 6 week scan, they saw an extra, empty sac and said it looked like a vanishing twin. The doctor cautioned the maternit21 may give a false positive because of this. At my 12 week scan, the doctor at the genetic counseling center said the test would probably be okay because the sac was empty so many weeks ago. I had the maternit21 performed. The results came back as inconclusive due to not enough fetal DNA. I’m also overweight at 5 feet and 145 pounds. Could the vanishing twin or my weight have contributed to my results? Also, I had a 2.9 nt reading at 12 week scan which I was told was in the upper range of normal but made me also very worried. I will have quad screening next Thursday at 15 weeks and possibly amnio, but I am sick with worry over the maternit21 results. Thank you for your feedback and time.
Also, I’m 35 years old, turning 36 in April. Thank you.
From the beginning, amnio was the only way to know for certain. NT, quad, & tests like MaterniT21 all have false positives and false negatives. Even if we were to treat the MaterniT21 inconclusive result as a screen positive, it still would mean you had a 1-in-5 chance that it was a false positive. Add to that the chance of a vanishing twin and your BMI and that increases the likelihood of a false positive. I regret that this promised accuracy of prenatal screening has only resulted in increased anxiety and more unknowns for you. I hope your providers give you compassionate care.
Mark,
Thank you so much for your quick and detailed response. This site is very informative, unlike so many others.
Hi Mark
I had the Panorama and Horizons testing done about 8 days ago, Im 13 weeks along. My Physician called today to tell me that I had too many maternal cells and that i would need to contact a number given to schedule an ultrasound as well as more labs. What exactly causes too many maternal cells to not have results back at all from these kinds of prenatal testings?
I’m not clear on what your doctor means by “too many maternal cells.” I can only infer what the doctor means is that you had a low fetal fraction, ie that the percentage of cell free DNA from the pregnancy was low. If that is the case, newer guidelines recommend considering an unreportable result as an indication of a higher chance for aneuploidy. Your doctor is correct that in this situation then ultrasound monitoring and the offering of other screening is recommended.
I appreciate your response. I was able to get somewhat of a suitable answer when I called Natera. The test may have been contaminated or there weren’t enough cells detected from my baby to accurately post results. Im a first time mother and a worry wart!! I have a better understanding of the tests due to your article though so my time was not at all wasted. Thank you again for taking the time with a reply
Dear Mark,
I’m trying to find any research that could possibly confirm to me that if the gestational age of my baby is a week younger than scan measurements (they did vague measurements at 12 week scan and couldn’t get nuchal fold measurements either), this could affect my quad test results. I have a ratio of 1:100. I can’t help thinking that the seven day difference could have skewed my quad blood results? I’m waiting for my harmony test results….very nervously!
Proper gestation estimation is needed for screening test results to accurately recalculate your odds. However, a week earlier or a week later, I cannot say how that would affect the reliability of your quad results. I hope your Harmony results are accurately relayed to you and hope you’ll consult this post to ensure you get the correct recalculation based on your Harmony result.
Hi mark. I am 15 weeks pregnant with first child and i am 32 and i will be 33 at the time of delivery. I had the ultrasound test at week 14 and my GP told me that everyrhing is normal till now and that my baby is about 9 inch in size. But now my GP called me and told me that in my blood test there is increased risk of down syndrome. I did blood test at about 9 week pregnant. Now i am really worry and couldnot think of anything. I have given two options for further test which i have to decide in 4 days. Does my baby has down syndrome and if it does what will happen if i give birth? What is the possibility of having down syndrome? Please suggest me..
The blood tests will not tell you for certain if your child has Down syndrome–only an amniocentesis can provide that certainty. It sounds as though you had conventional serum screening and not cell free DNA screening. Therefore, while your screening test may suggest an increased chance, it is still more likely than not that your child does not have Down syndrome. See this post for helpful links that may help you and your doctor in understanding these test results and Down syndrome.
Hi Mark- My name is Erin and I am a prenatal genetic counselor. I also found this new information from Mary Norton very fascinating. However, in reading your post, a few things came to mind that I wanted to point out. First of all, cell free fetal DNA is simply such a better test for chromosomes 21, 18, and 13. I know everyone harps on the false positive for cell free DNA, and yes! they certainly happen, but they do not happen near as often as false positives from maternal serum screening. I see upset patients weekly for abnormal maternal serum screening and of course the vast majority have healthy outcomes. One thing that I think makes inquisitive people, such as yourself, happy with serum screening is the fact that a ratio is provided for the chance of trisomy 21 and trisomy 18. (The report is much less diagnostic-appearing than cell free DNA results). But in my experience, the reality is that when many women receive the abnormal serum screen results from their OB office, they are just told they screened “abnormally high” for the condition. Its not until they get to me maybe a week later that they actually learn the ratio. (And yes- same goes for patients who are referred to me for abnormal cell free. Many of them think it is much more diagnostic than it is when they come to see me. But I think the difference is that a positive cell free, consider the age and condition, is almost always a greater than 1 in 10 chance its true, compared to a positive serum screen which can indicate as low as a 1 in 300).
But your post is primarily about serum screening being better at detecting things other than trisomy 21, 18, 13, and the sex chromosomes. Definitely true, because cell free DNA testing is reporting specifically on the amount of placental DNA testing for chromosomes 21, 18, and 13 (so it literally cannot comment on any other chromosome condition… unless you use MaterniT Genome… but we won’t get into that right now!) I think that fact that a positive result for trisomy 21 just increases the risk for trisomy 21 and doesn’t secretly increase the result for other less common chromosome conditions (like in serum screen), makes this testing more transparent and gives the patient a more informed consent.
Maternal serum screening measures different analytes and uses the amount and ratios of those analytes to come up with the chance for down syndrome, trisomy 18, (sometimes trisomy 13), and spina bifida. It cannot comment on the chance of there being a different chromosome problem. So in all of those cases where a different chromosome problem was identified, it was because the serum screen came back abnormal for one of the conditions listed above (and was incorrect). So do we consider that a false positive or a true positive? Someone once told me, serum screening is great at letting you know if something may be wrong, but it is not so good at placing the flag as to where the problem is.
At the end of the day, prenatal testing is simply not one size fits all. There are pros and cons to everything and possible outcomes need to be discussed in detail prior to doing the test. Hopefully genetic counseling will continue to grow and there can be more people armed with accurate information to dispel myths and help patients make informed choices that are right for them!
Thank you, Erin, for your thoughtful response. I am not a champion of any one form of prenatal screening or testing, but I am a critic of how cfDNA screening has been over-promised and over sold. If cfDNA screen results were limited to the three major trisomies, then perhaps cfDNA screening would be more transparent and offer more informed consent than conventional screening which can return a range of unknowns. But, as cfDNA labs continue to expand their panels, they too are reporting back a range of unknowns. That said, I agree with your final paragraph and appreciate your efforts to support and counsel your patients to make the right choice for them.
Hello, Mark!
I’ve read so many articles and studies on the different testing that is provided to diagnose/screen for Down’s Syndrome. I am 25 years old and I’m healthy. I’m 36 weeks pregnant with my 2nd child. My first born is only 11 months. When I went through the the sequential screening with my 1st pregnancy I was low risk for all trisomy. With this current pregnancy I’ve received a 1 in 190 chance of Down’s Syndrome. I was told the NT Scan and first trimester blood work was well. I was told the 2nd blood work is what gave me a risk. The GC said my protein levels were not far from the “median” but the fact the number pattern was up and down is what caused a risk. I took the Maternit21 and it came back negative. Since the NIPT test I’ve had 3 ultrasounds and no markers were found. I was told my ultrasounds look great. I’ve been a worried wreck and my anxiety is at an ultimate high. Do you thinking I should of did further testing? I asked the GC and OB if I should get invansive diagnostic done and they both agreed it wasn’t needed. Could my blood work been off because I became pregnant so fast after my first pregnancy? At 20 weeks they did say I had compete previa placenta which has now corrected itself. Could that be a reason?
Thanks!
See this post here with a link to a calculator for determining your negative predictive value, i.e. how likely it is that you are not having a child with a tested-for condition. With a screen-negative MaterniT21 result after having an adjusted chance of 1-in-190 your chances of your MaterniT21 being a false negative are less than one percent and it is greater than 99% that your screen negative is a true negative. So, it is extremely unlikely that you received a screen negative. Conventional screening like sequential screening have high false positives and false negatives and that is about all I can account for why you received a likely false positive with your 2nd trimester screen. Whether you should have had more testing depends on what you would do with the information.
Hi Mark, thanks so much for this article and for your responses to everyone’s questions in the comments section. I read through them all.
Right now, I am 12.5 weeks pregnant and just had my NT ultrasound and first trimester blood test screening. I am 34 years old and have had multiple miscarriages in the past. Much to my relief, the results from the NT/blood test combo came out negative for Down Syndrome and Trisomy 18 (1:5500 and 1:77000, respectively). The doctor did not provide any additional information about the other genetic disorder risks or heart issues.
Of course I was relieved, but my question is whether you think it may be useful at all to get the Panorama test done to ease my nerves, since Panorama can check for other genetic disorders? Unfortunately my insurance does not cover the Panorama panel test since I am not 35. Just not sure if it is worth the extra cost and if it can provide any more accuracy considering the values from my NT /blood tests. I understand Amino is the most accurate of all but I plan to skip it due to my negative results from NT. Any advice would be very helpful!
ACOG’ practice bulletin on cell free DNA only recognizes it for Trisomy 21, 18, and 13, and for indicating the sex of the fetus. Therefore, having the Panorama test would not report results recognized by professional medical organizations beyond what you’ve already received except for Trisomy 13. If you plan to skip amnio because of your screen negative NT-combined results, then if you had Panorama and it indicated anything, amnio would still be the only way to confirm those results prenatally. At the same time, Panorama and other cell free DNA screens are the most accurate for ruling out the conditions that they test for. If a screen negative from Panorama for the conditions it tests for would provide you peace of mind, then you may have it, but understand you are risking also being given a screen positive and then having to decide whether to confirm with amnio.
Hi Mark,
First of all, I want to say that it’s so amazing that you have created this website with so much valuable content. And the kind of personal support you provide to so many families, is just beyond my imagination! So thank you for that.
I’ll be 32.41yrs old at delivery. My first child will be 2.5yrs old at that time, and he does not have any chromosome problems. No one in my family or my husband’s family have any issues either. However, I received a “screen positive” result for Down Syndrome from my sequential integrated screening test with a 1:160 chance. My papp-a at 12weeks gestational age was 0.4 MoM which is low. And my hCG was 1.8. At 17weeks hCG is 2, AFP is 0.6, uE3 is 0.8, Inhibin is 1.6 and chance of DS is 1:160 which is higher risk than cut-off of 1:200
An ultrasound done at 13weeks did not detect any issues, although I don’t think the results mentioned anything explicitly about the nasal bone so I’m getting that checked.
I also took Natera’s Panorama NIPS test at 13 weeks, and that came in as low risk with less than 1:10,000 chance of T21, 18, 13, Monosomy, Triploidy, 22q11.2 deletion syndrome. But I’m very confused why NIPS came in low risk while sequential screen came in positive?
The reasons that I could think of were:
1. NIPS result is a false negative – which means sequential screen result is more accurate in my case, and only way to find out for sure whether baby has DS or not would be through Amnio. From our research it seems very unlikely that NIPS would give a false negative though.
2. NIPS does not check several other chromosomal abnormalities which the sequential integrated screening is picking up? Even if so, why would that raise the risk of DS in the integrated screening result? And if this screen positive is due to some other chromosomal abnormality, would Amnio detect those? How serious can those other abnormalities be?
Are there any other reasons why NIPS and integrated screening results don’t match? Do I need to go through Amnio or can we be assured that our baby is fine with these results?
If Amnio is the right thing to do, how much is the risk of miscarriage, or baby developing clubbed foot or any other deformities, etc.?
How long does it take to get the results from the Amnio? And by when should I get it done?
Thanks,
Asha
It is unlikely that the NIPS result is a false negative and for the conditions that NIPS screens for, it trumps the results of conventional screening such as integrated screening. The reasons for the difference is that there is a far greater chance of false positives with conventional screening than NIPS. As this post covers, conventional screening does identify other conditions beyond those that NIPS tests for; but in your case your integrated screen result was still for Down syndrome, so the negative NIPS trumps that. From the beginning the only way to know for certain prenatally is with an amnio, and an amnio can test for all conditions. The associated risk of miscarriage or fetal deformity is dependent on the experience of the doctor who would perform it on you and the facility where it would be performed at. It used to be a rule of thumb that the risk of miscarriage was 1%, but at certain hospitals, due to performing many amnios and having a lot of experience with them, there reported risk was half that, i.e. 0.5%. The soonest I’m familiar with amnio results being reported is within seven days, but I believe the norm is more like two weeks; again something that would be specific with where you had it performed if you choose to do so. All this being said, with the screen-negative NIPS for Down syndrome trumping your integrated screen result, whatever the risks associated with amnio by your doctor and hospital, they would be more than the chance your NIPS result is a false negative. I hope this helps.
Hello Mark. I am 36 years old pregnant with my second child. 2 weeks ago I had Panorama and combined first trimester screening. Panorama came back at low risk for DS and other chromosomal abnormalities but the combined first trimester screening came back at high risk for DS (1:5) due to the low level of protein in maternal blood (scan was normal). Let me just ad here that when I was pregnant with my first child we had the same results (low protein level) and high risk for DS (1:160). My son was born perfectly healthy. I am totally shocked and confused with the two results and don’t know what to think about it.
Please advise how accurate is panorama to combined first trimester screening.
I thank you in advance.
Joanna
When it comes to Down syndrome, your Panorama result trumps your combined first trimester screening. Panorama is far more accurate for Down syndrome than combined screening.
Mark, thanks for the article.
I need an advise wether I should do an amnio or not. I`m 28 yrs old, baby`s father is 42. I got the high risk of DS based on low papp-a level 0.144 MoM. NT and all other parameters are fine. I got results from Panorama test, all risks are low < 1:10,000. I`m going crazy and I can`t decide wether to do amnio to be sure or Panorama is accurate enough to give an answer.
Thanks
Your Panorama result trumps those of your NT combined screen, so in making your decision consider whether you would have an amnio having received a screen negative result that has a less than 1% chance of being a false negative and a greater than 99% chance of being a true negative.
Hi Mark – I was wondering if you could help me with my test results- my Nipt came back with a 96.87% chance of t21. My age at delivery will be 41 and my husbands will be 52- do you know if my husbands advance age too has any reason the percentage is so high?
While there is an association for increased chance for aneuploidies (like T21) with older fathers, I do not believe that is factored into the percentage reported to you. According to this online calculator, based just on your age, the positive predictive value of the screen result is 95% with a 5% chance of being false positive–only an amnio can provide a diagnosis. If you didn’t receive it with your test result, the resource at this link is the recommended resource about Down syndrome to learn more about that condition and available support services.
Thanks for answering my question and I have one more I was wondering if you could help me with? I was looking at my Nipt test results that came back as 96% for T21 and I had the blood drawn at 10 weeks 2 days and it says the fetal fraction was 4%. Do you think the low fetal fraction can mess the the positive test results? What do you think about getting the test again now that I’m further along, or just go with the results I have now and plan on having a baby born with DS?
Thanks so much!!!
Low fetal fraction has been associated with unreportable results, but then, unreportable results are associated with increased chance for aneuploidy. The accuracy of cell free DNA screening does increase with the length of the pregnancy, as more cfDNA is in the bloodstream as the pregnancy progresses. If you are planning on continuing your pregnancy with the expectation that you likely have a child with Down syndrome, this website has articles and books available for free for moms continuing pregnancies.
Hi Mark,
I just turned 38 two weeks ago, my claritest came back normal but my sequential screening 1st part showed high risk for Down’s syndrome 1:192 and the 2nd part showed high risk for Down syndrome 1:48. I don’t know if I should do the amnio to assure that my baby is healthy or I should just rely on the negative Claritest results. Please advise
Thanks
Carol
I’m not sure the accuracy of Claritest as I’m unfamiliar with that brand name, but if it is like most other cell free DNA screening tests, based on your age, you have a greater than 99% chance that your screen negative is a true negative. (see the calculator at this site for yourself). According to current guidelines, for conditions like Down syndrome, a screen like Claritest trumps conventional screening like sequential screening.
Hi Mark , I’m 38 years old, had the cfDNA test done at 12 weeks It came back negative but then I did the NTultrasound and it was at 3.3 the doctor recommended the amino,. I’m now 16 weeks , do you think It’s necessary to do the amino ? Thanks
I’m not sure why the doctor recommended an amnio. As this post covers, cfDNA has a very high accuracy, but for a limited number of conditions. According to the most current professional guidelines, cfDNA results take precedence over conventional screening for the limited number of conditions cfDNA screens for (T21, 18, & 13). Moreover, NT ultrasound, by itself, is not recognized as a valid screen for the conditions cfDNA screens for. However, if, in your doctor’s experience, he’s seen an association between a high NT measurement and other conditions not tested for by cfDNA screening, then perhaps that is why he is recommending amnio. Regardless, from the beginning an amnio was the only way to receive a definitive answer whether your pregnancy has a tested-for condition. However, many expectant women are relying on a screen-negative cfDNA result to avoid the risk of miscarriage associated with amnio.
Thanks for the quick reply, she said they recommend the Amnio to mom’s with abnormal test and over 35 and me being 38years old and with a NT ultrasound at 3.3 she said that it was up to me but they have to offer it , do you think the NT number is high enough for me to risk it ? Or is there a big chance that there’s something wrong with this numbers ,sorry I’m just confused . Thanks for all your help
I am not knowledgeable enough about the association with an increased NT measurement at 12 weeks and any other genetic condition. I would recommend speaking with a medical geneticist or genetic counselor. Contrary to the statement by your OB, since 2007, professional guidelines have recommended that all expectant mothers, regardless of age and screen results, be offered diagnostic testing. So, I would want to know more about what an increased NT measurement at 12 weeks is associated with before deciding whether the certainty of an amnio is worth the risk of possible miscarriage.
Mark, Thank you for providing this forum!! I am 13.5 weeks pregnant, Panorama from 10 weeks came back low risk, and pregnancy is from IVF with CVS type PGD testing of all chromosomes that also said embryo has a normal chromosome count. Doing nuchal fold ultrasound today, per advice of my OB, but she said it’s up to me whether I want the bloodwork part of the triple or quad screen or not. If nuchal fold is normal, I’m not sure what to say. What would that bloodwork test for that is not tested for by the other tests I’ve done?
Professional guidelines recognize PGD for conditions like Down syndrome as still just screening. The same guidelines do not recognize a nuchal measurement, by itself and without the blood test, as a valid screen for conditions like Down syndrome. Ultimately, the only way to know for certain is with an amnio. Prior to doing so, many women are having cell free DNA screening and relying on those results if they are negative. However, in your case, with a screen-negative result from PGD, that may be just as reliable as cell free DNA–something to discuss with a medical geneticist or genetic counselor.
Hello Mark,
I was just wondering if you might have any insight into this? I had the Harmony test done at just over 11 weeks. I was very relieved when results came back that I had a low risk of DS or any of the trisomy’s. However, the gender came back inconclusive. They offered to test the gender again at no charge, and it came back inconclusive a second time (at just over 13 weeks). I could not get anyone at the lab to speak to me, but they did speak to my Dr. They reassured her it did not put me at a higher risk of anything being wrong with the baby. However, I have not really been able to find anything in my research that shows people getting multiple inconclusive results on gender only. Usually it seems to be on the entire test. So just the fact that it seems to be so rare has me a little worried. Do you know what may cause this? Again, I am so relieved that everything else came back OK. Finding out the gender was just a bonus for me. I’m not concerned with the fact that I have to wait to find out the gender, I’d just like to understand what could cause 2 inconclusive results?
Unfortunately, I am unfamiliar with such an inconclusive result, as well. However, given that the lab would be exposing itself to liability if it were wrong in assuring you the inconclusive result is not associated with any chromosomal condition, I hope that provides some comfort.
Hy mark. First of all i wanted to say thanks for the time you take in answering with such clarity and patience all of the questions.
I am currently 31 yo, 5 weeks pregnant.
One year ago i gave birth to my first child, she died 50 min after birth due to treacher collins syndrome that was only diagnosed after birth (genetic testing done to her after death), we both parents tested negative for the specific mutation. With her we did extended panorama at 13 weeks (due to micrognathia seen in 12 w US); it came back low risk for each condition tested.
My questions are:
1. We are planning on doing NIPT with this pregnancy also; will the accuracy lower due to “contamination” from my previous pregnancy?
2. Which “brand” of nipt in your expierence you recomend?
2. Do you know of a prenatal test that we can do to rule out treacher collins this time? (Preferably non invasive, but any other also so i can ask my ob about it)
Thanks
My condolences on the loss of your first child and I wish you well with this pregnancy. My responses to your questions in order:
1. The accuracy will not be affected from “contamination.” I initially thought cell free DNA from the pregnancy remained in the bloodstream and could be picked up in a subsequent pregnancy. I’ve since learned that cell free DNA quickly leaves the mother’s bloodstream after birth.
2. It is near impossible to recommend one “brand” of cell free DNA screening over another due to the fact that none of the labs have shared their actual experience with testing large populations outside of carefully controlled studies.
3. I do not know enough about treacher collins to know whether conventional screening, i.e. maternal serum screening like the quad test, has been shown to have an association sufficient to indicate treacher collins. The only prenatal test that provides certain information on all conditions is an amnio, which is invasive.
Thanks so much for the clear responses and the good wishes.
Hi Mark,
Thank you for providing this valuable information. I hoped you might be able to share additional insight to our situation: I am 38 years old and expecting my second child on my 39th birthday. We recently completed the Progenity test (at 11 weeks 0 days) and it came back with an abnormality detected for Monosomy X. The performance of the test for Monosomy X was explained to us as having 95% “sensitivity” and 99% “specificity,” but the results also stated a positive predictive value (“the chance for a patient with a positive result to have an affected pregnancy”) as 9%. So does this mean that, at this point in time, there is a 9% chance of our baby having Monosomy X (essentially that 9 of 10 babies testing positive for the abnormality don’t actually have the syndrome)? If this is the case, are you able to explain why the results show so many false positives? Could my age be a factor? Does the 9% chance differ depending on our specific circumstances? I’ve been trying to contact Progenity for more information, and we will be scheduling a CSV (which also terrifies me) to confirm the results. In the meantime, it has quickly become quite a stressful situation for our family. Any clarity would be much appreciated.
1.) tests like Progenity are not recognized as accurate screens for conditions like Monosomy X due to there being insufficient-sized clinical trials to show its reliability; 2.) you are correct that the 9% positive predictive value (PPV) means you have only a 9% chance that your test result is a true positive and you are carrying a child with Monosomy X and a 91% chance that your test result is a false positive and your child does not have Monosomy X; 3.) the reason for the false positives (and false negatives) is due to tests like Progenity testing DNA that comes from the placenta and not necessarily from the fetus; for conditions like Monosomy X, there is a phenomena called “confined placental mosaicism” where certain cells in the placenta may have a condition like Monosomy X, but the fetus does not; 4.) because a CVS also tests cells from the placenta, it has the potential for reporting false positives if the sample of cells taken is from a region of confined placental mosaicism; for this reason, amnio remains the better diagnostic test.
Hello Mark,
This is the first article that gives me helpful insights into my options also I haven’t had my genetic counseling session yet. I’m 37, first time pregnant. Had a vanishing twin diagnosed at 7 weeks, not seen anymore on 12 weeks US, My doctor recommended doing the California Screening incl. 1st trimester blood draw, NT and quad in 2nd trimester. First tests came back normal, combined results showed high risk DS at 17weeks, 5 days with 1:110. My doctor sends me for amnio but I’m hell of scared and insisted on NIPT. Waiting for results, hoping to get them back before next US and genetic counseling at 18weeks, 5 days. Do you think NIPT can still be affected by vanishing twin? Are there any further markers on US that can recalculate the risk assessment? Thanks so much for your support for all these women.
For conditions like DS, your NIPT result will trump the screening you have done so far and any ultrasound finding. The research is unclear on the effect of a vanishing twin on NIPT, but because that could be a source of cell free DNA, and because many fetuses with conditions tested for by NIPT naturally miscarry, I believe the vanishing twin could account for a false positive. On the other hand, if you get a screen negative result from NIPT, the chance that that would be a false negative is very low. All things to discuss with your genetic counselor once you have the NIPT results.
Hi Mark,
I am 11 Weeks, 2 days pregnant with identical twins and just got the results of my NIPT from Counsyl. The results came back positive for Trisomy 18 but they are “borderline value.” What does this mean? I spoke with a genetic counselor from the company but I’m still unclear. I’m 38 (will be 39 at time of birth). The pregnancy was through a frozen IVF cycle. We transferred 2 frozen embryos (the embryos were frozen when I was 34 years old). Only one survived but split into two, so the twins are identical. I just don’t understand what a borderline positive result is. Shouldn’t it either be positive or negative for T 18? My doctor recommended an amnio, but I’ll have to wait another 4 weeks, which is going to be unbearable. Are there other tests before then? I see my OB for the first time next week ( I was under the care of my RE before) but even that seems like such a long time to wait. Thank you in advance for any information.
I’m not sure what Counsyl means with “borderline value” and I would have your OB ask Counsyl for an explanation. According to this calculator, your chances of your screen result being a false positive are 43%, with a 57% chance that the result is a true positive. However, the accuracy of screens like Counsyl are not recognized for twins. With Trisomy 18, often physical signs can be seen on ultrasound, which could be done at anytime while you wait for the time to have an amnio. Depending on the ultrasound, that may corroborate the screen result or further suggest its a false positive.
Thanks for the response, Mark. Ultrasound at 13 weeks showed no signs of Trisomy 18, but I know it’s still early. The combined first trimester screening showed chances of Trisomy 18 as 1 in 18,000, but the risk of Downs was 1 in 81 (a positive result). I’m so confused by these tests. My amnio is scheduled for next week so hopefully I can get some answers.
Just wanted to update for anyone else reading that my borderline positive result was indeed a false positive. I did an amnio a few weeks ago (along with the microarray) and both twins tested normal. I contacted the genetic counselor at Counsyl to let her know but didn’t get a response. My OB thinks the positive NIPT test may have been due to the embryo initially transferred that didn’t “stick.” Anyway, just wanted to update my post in case others are in the same situation who is lead to believe that these tests are 99% accurate.
Thank you for updating us. One of the challenges to the claimed accuracy is the inconsistency labs have in following up to confirm their screen results. I appreciate you making the effort update Counsyl with your results. Best wishes for a healthy pregnancy, delivery, and surviving twins (I’m a twin myself).
Hi. I had the Claritest at 10 weeks and it came back positive for a micro deletion called Di George Syndrome. From what I have researched Harmony doesn’t check for micro deletions. My doctor won’t do a Panorama to recheck ,which is done at 12 weeks and wants to go to Amniocentesis at 16-20 weeks.
My labs were given to me in someone else’s chart!!! So I requested rechecking the Panorama just in case it isn’t my sample. They refuse to do the Panorama. I was never offered choices they went straight to the Claritest and never gave me info on it
How much would a Panorama be cash? Maybe for some peace of mind it would be worth it ?
They also weren’t able to tell me if a regular amnio checks for micro deletions, or tell me the false positive rates of the Claritest. It seems to be very new. Do you have any information on the Claritest and these micro deletions that are not checked by Harmony? Seems like micro deletions aren’t talked about much.
I forgot to include that I had a “normal” nuchal ultrasound done
I am not familiar with nuchal screening being recognized as a screen for microdeletions, so I don’t think the nuchal results would effect your positive predictive value or false positive rate for your Claritest.
I am unsure what Panorama would charge, but you could contact the lab itself to find out. Tests like Panorama and Claritest are not recognized by professional organizations as being accurate screens for microdeletions due to the published studies being too small of a sample size. By selecting 22q for condition tested and entering your age at this online calculator, you can get an approximate false positive rate. An amnio tests your fetus’s DNA and could test for microdeletions if the testing lab is instructed to do so; if they do a simple karyotype, that will not be enough.
Hi Mark! I have come across a number of your posts while researching the benefits and shortcomings of NIPS. I appreciate your transparency and accessible language. I am currently pregnant and scheduled for my blood draw next week – Materniti21 is the one covered my insurance. I will be 11 weeks 4 days gestation and I just turned 36. I would like to know which abnormalities would fall under the “Other” category that NIPS are unable to detect? I assume Open Neural Tube Defects (ONTD) are included, but are there others as well? I have made several (unsuccessful) attempts to register for a Medscape account so that I can view the source article you link in your post above. I would greatly appreciate your insight here. Can you provide the title of article so that I might locate it elsewhere, as well as a summary of the abnormalities that fall under the “Other” umbrella?
I have been told by my doctor’s office that my insurance company would not cover the first portion of the sequential screening blood work if I am getting the NIPS, because it would be considered a replication. They said I could get part of the second portion of the sequential screening blood work that will detect the likelihood of ONTB (likely AFP, as the others are primarily associated with trisomies from what I can gather). However, I want to be fully informed. If there is a compelling reason to get PAPP-A measured, I would like to be aware of it ahead of time. I have read that low levels of PAPP-A may be associated with risk factors such as growth restriction, preterm delivery, and stillbirth. I am worried I may have to fight with my insurance company for coverage if I decide to get the PAPP-A measured. Thank you very much for your help!
The study about which the article reports is available for free online; see this link. Actually, in reviewing the study, it did not address ONTD, but was making the point that sequential screening identifies even more chromosomal conditions than cell free DNA. Those “other” chromosomal conditions were: other trisomies, including trisomy 2, 4, 6, 7, 8, 9, 10, 12, 14, 15, 16, 20, 22; trisomies for multiple chromosomes; triploidy and other polyploidy; unbalanced Robertsonian translocations; large duplications and deletions; extrastructurally abnormal chromosomes; and other, including other cases of reported CVS mosaicism, other translocations, additions, duplications, inversions, and ring chromosomes. So, your doctor’s and insurance’s position that the first trimester testing of sequential testing is duplicative of cell free DNA is incorrect.
Thank you for this information. It certainly puts things in perspective. I did not see a link in your reply above. Would you mind providing it again?
Thank you for alerting me to that. I’ve edited my comment to include the link. It can be accessed here, as well.
Hi I had a triple marker test done which reported PAPP-A-1.4mIU/ml, 0.62 MOM,Free beta hcg-140.9ng/ml- 3.17 MOM, NT MOM-0.97. they reported a calculated risk for Trisomy 21 .
Trisomy 21 +NT Risk-1:224.
I then went for a NIPT at 12 weeks 6 days which showed low risk.
My doctor suggests to go for next ultrasound and no need to perform Quad screen test.
What do you suggest.
For the conditions it tests for, which includes Trisomy 21, NIPT trumps other screening tests, so your OB is correct that the quad is not recommended for T21; however, NIPT does not screen for open neural tube defects, so the quad would still be recommended if you wanted to screen for that.
Hi Mark, thanks for an informative post. I am 38 years old and 21 weeks pregnant with my second child. My first born is a healthy 8 year old. I had the cell free fetal DNA test in my 1st trimester which came back negative for all the genetic conditions it tested. We did detailed ultrasounds in 1st trimester as well as at 20 weeks. At the 20 weeks detailed ultrasound, they found 3 bilateral Choroid plexus cysts in my baby’s brain. No other anatomical abnormalities were found. Since CPCs are soft markers for Trisomy 18, I have been losing my sleep over this. The genetic counsellor advised me to take amniocentesis for peace of mind, but my obgyn is against doing that due to the risk of miscarriage. I am at a loss at what to do. Apart from the amnio test, is there any way we can find out if there indeed is an increased risk for Trisomy 18? I have been reading about the different types of genetic tests and AFPs and what not. However, I don’t think we did anything other than the blood fetal dna test and the ultrasound. Are these reliable enough? My obgyn has ordered another detailed ultrasound at 28 weeks but it will be too late to terminate the pregnancy if they did find something.
What would you suggest? Thanks much in advance! Sheri.
Current medical guidelines recognize cell free DNA screening as taking priority over conventional screening, like AFP/Quad and ultrasound soft markers. If you’re child had T18, it had it from the beginning and did not develop it after the cfDNA screen. But, I understand that the UT findings are concerning. You could have another cell free DNA screen and if it, too, is negative for the tested-for conditions, that would be pretty reliable.
Hi Mark
I found your article to be quite interesting and your replies to so many pregnant and (emotional) women very honest and genuine. You have very good bedside manner!
I have a healthy 3 year old and I am 11 weeks today with my 2nd. I was offered the Natera Horizon Test at 9 weeks. I never heard of it and only had the Harmony test with my first.
My Doctor called yesterday with bad news he said.
There weren’t enough cells to determine the DNA which indicates this baby has some chromosomal abnormalities. I have my Nuchal Trans test at 12 weeks and he said the reality is this:
This test is very new and so far has only dealt with 20 other patients. He found his last patient who had my similar results to have a healthy baby just now. He says, the false negative is pretty rare but it does happen. He thinks I should still have the NT Test and lets see what happens there and if surprisingly that comes back OK he may want me to have the CVS test done and if further an Amnio.
He said ultimately he isn’t so sure that this Horizon test was 100% accurate. My question is why was it offered to begin with? I am 33 and will be 34 when this baby is born. What is the difference between this test and the harmony test? And is the Horizon test even FDA approved? I feel like reading these boards and others it’s done nothing but worry women and even end pregnancies based on inaccurate results.
thanks so much for your time Mark
There’s a lot that doesn’t add up with what your doctor relayed. Natera’s Horizon test is a carrier screening test, meaning it screens for conditions that you may be a carrier for, not the fetus, necessarily. I expect, instead, what test you had was Natera’s Panorama screen, which screens for the same conditions that Ariosa’s Harmony screens for, e.g. Trisomy 21, 18, 13, and sex (the only conditions any of the screens like Panorama/Harmony are recognized as being accurate for). None of the screens like Panorama/Harmony are FDA approved. Medical guidelines do say that inconclusive results, like yours, should be treated as “high risk” since some inconclusive results end up being true positives, but the false positives for inconclusives are much higher than if you had had an outright screen-positive result. Further, the same guidelines recognize screens like Panorama as taking precedence over any conventional screening like NT-combined for the limited conditions Panorama is recognized for (though NT-combined screens for more conditions, just at a lower accuracy rate) and the guidelines recommend against doing multiple screens for the same condition independent of one another as it can lead to conflicting results and more confusion. If what you had was an inconclusive Panorama result, then you could be considered at an increased chance for the conditions Panorama tests for. The recommendations would be to be referred to genetic counseling (where available), be provided this booklet on understanding Down syndrome, and then consider diagnostic testing if you want to know for certain. Feel free to pass on this post and the fact sheets linked therein to your provider.
Thank you Mark! You are correct – I did have the Panorama test. Thanks for your reply 🙂
Hi Mark,
I came across this article today after having my 20 week ultrasound and getting some conflicting information on whether NIPT trumps quad screen. I am currently 40 (41 at delivery).
I had the Panorama test for my first son (now 18 months) and it was negative (1/10,000) across the board, however I tested positive for sequential screening (1/140) After talking to my genetic counselor and not having any other markers I opted to trust the negative result and was thrilled to have a healthy baby boy born in March 2016. Fast forward to this pregnancy. I opted again for the Panorama test and was <1/10,000 for Trisomy 21,18,13, Monosomy X, low risk for Triploidy and <1/13,000 for 22q11.2 deletion syndrome. I had NT test done at 12 weeks and it measured 1.7mm. I decided not to do first trimester screen and marked the box on the second trimester screen that I had NIPT and do not report out for Trisomy 18 or Down's. I only did the quad screening as my doctor recommended it since it also tests for neural tube defects, abdominal wall defects.
Unfortunately, I got a call back from my OB and they did report my risk and it was 1/25 (I am not sure if it's for Trisomy 18 or Down's) as I wasn't really concerned due to negative NIPT. I did have my genetic counselor look over the levels in my quad and she said that my Estriol and Hcg were off but not by much. She suggested to wait for the 20 week ultrasound.
I had my 20 week ultrasound today and everything looked great except I have SUA (single umblical artery) My doctor said it is not correlated with increase risk for chromosomal abnormalities. However, when I told the doctor about my results from the quad screen and the negative NIPT he disagreed that NIPT trumps the quad screen. He said based on data there is a 2% chance of having a baby with chromosomal abnormality when someone has a negative NIPT and positive screen through the California Prenatal screen.
He said he wasn't trying to push for amnio but that he disagree's with the thought that NIPT trumps quad screen. I know the only definitive answer will be to have the amnio and I wish the state of California hadn't reported out the quad screen as I requested as I'm now torn whether I should have the amnio.
Are you aware of the 2% risk he is referring to with a negative NIPT and positive quad screen. Would you agree that a negative NIPT along with no other markers would be more accurate than the quad screen?
According to the ACOG guidelines, NIPT trumps all other conventional screening, like quad screening, for the conditions that NIPT screens for. As this post recounts, there remain some chromosomal conditions not detected by NIPT, and therefore those conditions are not trumped by a negative NIPT screen. However, most of these conditions detected by conventional screening and not NIPT are of larger chromosomes with most naturally miscarrying and showing malformations on ultrasound when possible to be seen. I would confirm what the quad result was 1/25 for; if it is for T21, 18, or 13, then your Panorama result trumps your quad result. I’d also ask what your doctor is basing his 2% risk on; it may be the very study cited in this post, but I’d be curious if he has another source.
Hi Mark,
This is a fascinating and really helpful thread, thank you.
I’m 35, 13 weeks pregnant with my first child (I did have a loss about 6 years ago). I just received my MaterniT21 tests and was low risk for all the Trisomies but it did come bac “suggestive of an additional X chromosome, which may be found in pregnancies with Klinfelters Syndrome.” My 12 week scan and all other blood work has been perfect and my Perinatologist said the PPV for this test is 33…and that the overwhelming likelihood is that my baby is not affected. She said these tests are very accurate with some issues, but very unreliable with the sex chromosomes.
I’m having my amino at 16 weeks, but was curious of you have heard much about false positives when related to the sex chromosomes.
Thanks again!
Katie
Based on your age and the suggestion of possible Klinefelter syndrome, this online calculator computes your PPV to be 30% with a 70% chance that the test result is a false positive. Your perinatologist is correct that the odds make it far more likely that your child is unaffected. Professional medical organizations do not recognize tests like MaterniT21 as being accurate for sex chromosome conditions due to the lack of proven accuracy. In a study of one large health system that I’m familiar with, the results were that false positives occurred 3/4 of the time.
Hi Mark,
I’m 39yo and 22 weeks pregnant with my first child. I had the Horizon and Panorama test done at around 11 weeks, and the results came back <1/10,000 for all the risk factors. However, it as discovered that I was a carrier for a biotinidase deficiency, so my husband was tested, and it turns out he's a carrier as well. Not the worst news, but at our recent 20 week ultrasound, our doctor suggested we talk to a genetic counselor.
When the genetic counselor's office called to make an appointment, they suggested I get the nuchal translucency test, something I'd never heard of. I have called my doctor's office and am awaiting a returned phone call from my doctor herself, but the person who picked up the phone call confirmed I had not had a the NT test done.
My questions are – is the NT test something that should have happened, and since it didn't, is there a risk of Down's Syndrome that I am unaware of? From what I'm reading, the NT test should be done at 11-13 weeks, so I'm not sure why the counselor's office is suggesting I do it now. The only abnormality that showed up on the 20 week scan was one kidney dilated at 6mm.
Also – thank you for this post. Very helpful!
Unfortunately, your case sounds like an example of where changing practice guidelines has resulted in some OBs offering just cfDNA screening (like Panorama) to women considered “high risk” instead of also offering conventional screening like the NT-combined test, which screens for more health conditions. I suspect they are recommending the NT now since it may have an association with the deficiency both you and your husband are carriers of (I’m not sure if NT has that association and it’s something you could ask your health care providers). All that said, when it comes to the conditions tests like Panorama are recognized for (just Down syndrome, T18 and T13), then those results trump any conventional screening results–meaning your Panorama results are more reliable than the NT screen for Down syndrome. Since you received a screen negative, your odds of the Panorama result being a false negative are less than 1%.
Hi Mark,
Your blog has been a wealth of information and your replies and follow ups are so appreciated. I am currently 37 years old and will be 38 when I give birth. I have 2 healthy children and this pregnancy is my 3rd via IVF following a 5 year gap from my youngest.
At my 12 week scan my NT measured at 3.6 mm and the Dr was concerned. I had the Harmony blood test done and results came back as Low risk 1/10000 for all T21/T18/T13. Dr seemed happy with those results and said no need for any further concern.
I wanted to ask how many false negatives using Harmony specifically have you come across.
As well at an ultrasound at 17 weeks one of the babies kidney’s was dilated, Dr did not seem overly concerned. But I read it could be a very very soft marker for Down Syndrome. I have an anomaly scan scheduled at 19 weeks, is there anything I should be on the lookout for. I am naturally a worrier and haven’t been able to really enjoy this pregnancy despite the negative Harmony tests.
How concerned should I be? Is there any other way to confirm my baby does not have any abnormalities without doing an amnio??
Thanks so much for your reply!
CE
While I have another post that critiques the marketing of these tests being “99% accurate,” in your case, they are actually even greater than 99% accurate for the conditions they screen for (see this negative predictive value calculator where, when entering your age and Down syndrome as the condition, it returns a greater than 99% chance that the result is a true negative). That said, I am aware of two instances where a cfDNA negative result was a false negative. The only way to rule out any abnormalities would be an amnio and a thorough second trimester ultrasound to look for any physical abnormalities. Given your Harmony result, for the conditions it screens for, it would be very unlikely it is a false negative. One option would be to have a different cfDNA screen performed (MaterniT21, Panorama, etc.); if that came back negative, that would make the odds even rarer for the results to be false negatives. But, I would not recommend the second cfDNA screen as it is of limited value. I wish you well with your pregnancy and thank you for the kind remarks about the blog.