Your MaterniT21 test is NEVER positive

IMG_1457And it’s NEVER negative, either.

A week ago, I attended the American College of Obstetricians & Gynecologists’ (ACOG) Annual Clinical Meeting in Chicago. It was a quick trip, where I met with each of the non-invasive prenatal screening (NIPS) laboratories before getting back on the road to return home. Something I saw there prompted the title of this post.

How accurate are the new blood tests for Down syndrome?

This past weekend was the Kentucky Derby. So, odds have been at the forefront for all us Louisvillians: which horse to bet on, what odds are they going off at, and can we couple them with two or three others for an exotic bet: an exacta, trifecta, or superfecta?

This thinking about odds should also be kept in mind for every woman accepting non-invasive prenatal screening. Be it Sequenom’s MaterniT21, Ariosa’s Harmony, Illumnia/Verinata’s verifi, or Natera’s Panorama, a very critical point needs to be appreciated:

None of the new blood tests provide a definite answer.

None. Of. Them.

No matter how the results are reported, you should understand that if you are pregnant, and you get a non-invasive prenatal test result, it is never positive or negative.

NIPS tests are screening tests. They are a recalculation of the probability that your child may–emphasis on MAY–have Down syndrome (or one of the other conditions they test for). Every one of these tests has false positives and false negatives.

What are patients being told?

But note what Sequenom highlights on its booth for its MaterniT21 test:

IMG_1458

 Clear, direct results

+ Positive or negative results

- No risk score!

Sequenom highlights this as though it’s a good thing. In fact, it’s against ACOG’s own professional guidelines.

When ACOG changed the standard to offering prenatal testing for Down syndrome to all women (versus only those over the age of 35), it emphasized that results should never be relayed as a “positive” or “negative.” Instead, results should be presented as a probability calculation (or “risk score”).

But, here is Sequenom, the market-leading NIPS company, highlighting that it reports its results contrary to these professional recommendations, as though it is a selling point for its testing.

Invasive testing is the only option for a definitive answer.

ACOG’s statement on NIPS recommends that patients should be counseled that confirmation is needed with diagnostic testing because no NIPS test is a true positive or true negative. But, what is a mom to think when her test result is reported by the testing lab as a “positive” and not a probability ratio?

Sequenom is not the only lab to suggest its test results are more accurate than they actually are. But if you are receiving these test results, you need to understand that none–NONE–of the new blood tests provide true positives or true negatives. You can only gain that certainty through invasive testing.

NIPS tests remain just screening tests. They are never truly positive or truly negative. Get confirmation through invasive testing if knowing for sure is what you thought you were buying with a NIPS test.

Comments

  1. Madeline Levy says:

    I would just like to say say that my Sequenom rep is very clear that MaterniT21 is a SCREENING test. When counseling my patients, I’m confident in saying that MaterniT21 has 2.14% “positive” results, much like the test it will eventually replace, the amniocentesis. The other tests have far more issues with off-base calls, like Verifi with almost 8% of the results “aneuploidy detected” or “aneuploidy suspected”, leading to more invasive screening.

    • What risk score are you able to provide your patients based on your MaterniT21 results? I.e. does Sequenom provide a risk score (it’s marketing booth says it doesn’t). I ask because most would hear a high detection rate and believe that is their personal odds for having a child with Down syndrome, e.g. 99.5%. ACOG PB 77 recommends that when discussing screening results they should be delivered as a probability, e.g. 1-in-1,000, 1-in-250. Can you provide that probability based on the results provided by Sequenom and do you?

    • Thanks so much for posting this. I just had a horrible experience with a sequenom lab. My wife and I waited three and a half hours for a blood test and ultrasound while they ran around to find a nurse available. They then sit us down and the first thing they say is “you tested positive for DS” ?? – only to backtrack after our shock and state that we have a higher risk factor. I was furious with how it was messaged to us.

  2. Mr Leach, first let me thank you for your website. It seems to be very informative and helpful. My particular comment, or question rather, is related to materniti21 and panorama, both of which my partner has had. She is considered “high risk” at 43 years of age and her first pregnancy. NT scan came back at 1.81, and both tests came back as low risk, or 1:10,000 risk of having down’s syndrome, or any genetic disorders that those tests look for. We seem to be at very low risk for the child being born with down’s etc. which is our biggest fears. My concern is that these tests do not take into account her age. Do you know of or have any data showing the increased risks as age might increase the chances? Or are these tests taking her age into account?

    Thank you for your help on this topic. I’m sure as time goes on, more data will be available for the general public or those not in the industry.

    • Phil–my understanding of MaterniT21 and Panorama is that they do not factor in the mother’s age as they are looking at the genetic material from the pregnancy itself. My understanding of the first trimester nuchal translucency-combined test is that maternal age is factored into the algorithm that reports the probability assessment. As shown in the table at this post, your partner’s baseline chance for having a child with Down syndrome based on her age is between 1:85 and 1:35 (the numbers reported weren’t specifically for age 43, but 40 and 45). Therefore, the NT result of 1:81 likely was for a lower chance than just her baseline chance. With both MaterniT21 and Panorama returning results of 1:10,0000, that is a remarkably lower chance, and the ability of those tests to determine which pregnancies are not carrying a child with Down syndrome is more accurate than their ability to determine which pregnancies are carrying a child with Down syndrome. Given that you have three screen results showing a much lower chance than your partner’s baseline chance according to her age, it would seem more likely than not that the child does not have Down syndrome. I would recommend you discuss your concerns with a genetic counselor.

  3. One thing you’re missing is that maternit21 is only offered to women who are high risk. It is not a general public screen, thus the lack of A risk score result.

    • It is only supposed to be offered to high risk women, but providers admit to doing otherwise. Regardless, it’s a screening test and ACOG practice bulletin 77 says to not report results as “positive” or “negative” but as a risk score. Reporting results as “positive” or “negative” is factually wrong and contrary to professional guidelines.

  4. Hi Mark,

    As an expectant mother will you please explain the issues with these assays and why they are not reliable? I was so excited for it and now am coming across alternative information. thanks

    • The issues with the non-invasive prenatal screening is that they still report out false positives and false negatives. As a result, while they remain the most accurate screening test for patients considered high-risk, their results still hold the potential for being false. Only through diagnostic testing can a patient know to a near certainty whether their child has a genetic condition.

      • Diagnostic tests all have false positive/negative rates. Nothing is 100% definitive and anything in the hands of humans is subject to error.

        What I’m curious about is the issue you take with this assay. Are you saying that fetal DNA is not in maternal circulation? Or that it cannot be isolated?

        I’m not sure how it’s done either. PCR?

        • My issue is the same as shared by the ISPD, ACMG, ACOG, and NSGC, and an editorial in the NEJM: that we don’t know what any of these tests actual accuracy rate is because none of the labs have been transparent with their data. Specific for this post, my other issue is that some of the labs report their test results in language that lends itself for misunderstanding by both the physician and patient as to the accuracy of the testing. That said, more and more women are relying on these results instead of having a diagnostic test because NIPS results remain more accurate than any other screen and the expectant mothers would prefer to avoid the risk of miscarriage with diagnostic testing.

          • Ok, I thought you might understand how the test works and where the risks lay specifically with the assay itself, which is the actual issue here. I’ll keep looking. Thanks.

          • Feel free to report back what you find as I would be interested as well. Thanks.

          • I did a bit of searching and I ran across an article (linked below), which you have probably seen, that addresses at least one aspect of what I’m looking for as best as I can understand it without a strong background in genetics. Based on what I’m reading it is extraembryonic tissue cells that are tested and apparently the genetics here can differ from genetics of the fetus as far as aneuploidy goes?

            “it is well known that the cells originate from ‘extraembryonic tissues’ around the fetus so aneuploidy status may not always be identical to the genetics of the fetus.”

            I’m not sure why that is the case. Questions that come to mind is how often is it not identical? Knowing the answer to this could contribute to a false/positive risk number I would think. Further, this is the same issue that comes up with some invasive procedures, correct? -Confined placental mosaicism and perhaps other genetic variations that I’m not clued in about that can present as false positives in other testing.

            This does not address assay issues either regarding specificity and sensitivity. For this reason alone of course women should continue to on with standard screens. I can also understand why people are concerned about some of the false advertising here. I get that now.

            “http://www.sciencedaily.com/releases/2013/04/130408133754.htm

            http://en.wikipedia.org/wiki/Confined_placental_mosaicism

          • Gina–thank you for sharing this article. My understanding is that because the new blood test is of “extraembryonic tissue” the best accuracy it could ever achieve is that of a CVS, which is the first trimester diagnostic test. But because CVS also takes samples from extraembryonic tissue, it has a higher false positive/negative rate than amniocentesis, which samples actual fetal cells found in the amniotic fluid. Thank you for sharing further information on the new tests.

  5. Thank you very much for your work on these new testing procedures.

    How accurate are these test in determining the gender of the baby? Is this aspect of the test also a “screening” or is it more like a positive/negative result (Eg. male or female)?

    • I am not for certain, but my understanding is that the test results for gender, particularly if male, are even more accurate than for aneuploidy. Your physician can check with the lab on the level of certainty.

  6. My Question is what can be done after you receive the results. The result is not going to change the fact that you are pregnant and you want to have a baby. Those results are going to stress you out and if your body is having down syndrome what are you going to do. Is there any thing offered once I get the results showing down syndrome. My doctor called me and told me that since I am 39 years old and my other blood test came back with some factors showing the need for further testing. Thy offered the test T21 or amniotic. Now I am sitting and thinking about it and I think I will refuse all the tests because those tests are not 100% and they are not going to change the fact that I am pregnant and also that I want to have the baby no matter what the baby has or looks like. Those tests are not going to change enything for me or my baby.

    • This is a common decision process many parents follow: I don’t plan on changing anything about being pregnant so I do not want the added anxiety that comes with testing. That said, many expectant parents do appreciate knowing for certain beforehand so they can prepare themselves and their loved ones. If you do want to know for sure, then tests like MaterniT21 can help in deciding whether to have an amnio, as many mothers are now relying on a negative NIPS result to avoid the risk of miscarriage of an amnio (though as you say NIPS is not 100%). Regardless of what further testing you may or may not pursue, since you’ve already had an early indication from a test, I hope you do receive good prenatal care with heightened ultrasounds and monitoring so that if there is an associated health condition, like a heart defect, that is identified early and plans can be made for delivery and neonatal support.

  7. Dragomira says:

    I took the MaterniT21 – I am an expectant mother, 34 and tested low risk at the Nauchal Translucency Combined first trimester test, however, tested high risk at the second trimester screening. MaterniT21 was negative for DS, with I was told 99.9% accuracy rate, and 5% margin of error. Because of the contradicting results in these screening tests, I am going for amnio. I am curious if you have a possible explanation why results can point in such different directions. I understand those are different tests, but would you give more weight for accuracy to one versus another? My anatomy scan was great, no indications there of DS or any other issues.

    • My explanation is that all three–nuchal, quad, & MaterniT21–are screening tests, meaning they have false negatives and false positives. However, the false negatives are far fewer than the false positives, and particularly so with MaterniT21–meaning, it is more likely that a “positive” is false than a “negative” is false. Based on your screen results, the statistics would say you are far more likely to not be carrying a child with Down syndrome. Please share your amnio results as I’m sure others are curious about the outcome. And, regardless of the outcome, I hope the procedure goes well and that you receive counseling and support.

      • dragomira says:

        Thank you, Mark. I will share. It will be grueling several days before we know but I am trying hard to stay calm and strong.

        • I did amnio after much deliberation – the genetic specialists at my hospital didn’t seem to think it is necessary due to previous reassuring result from Maternit21. The good news is my baby is totally normal. Largely, they thought of the quad test as being the most unreliable of all screening tests.. To sum up, I guess I am part of the stats where the non invasive blood testing seems to have been accurate..

          • I’m glad your procedure went well. Many women are choosing to rely on a negative NIPS result to avoid the stress of a diagnostic procedure, the result being that the number of diagnostic procedures are plummeting. I hope the remainder of your pregnancy goes well and you enjoy it!

  8. Mcblinkie says:

    There are also quite a few women that have screened positive for their baby having Turner Syndrome (me included) through NIPT such as Maternit21, and amnio results or tests after delivery have shown the baby to be completely normal.

    As women age we can lose an X chromosome due to age related drop off so women over 35 taking these tests should understand that the false positive rate for sex chromosome aneuploidys is actually much higher than the percentage the laboratories report. Once I realized that these tests have not had any independant studies but use their own lab results to determine sensitivity and specificity I became much more sceptical of the use of these as an ‘almost’ diagnostic screening test. My test results through Verifi only showed a negative or positive result, when I asked for the specific numbers the lab would not release that information to me. It seems clear to all us women that the labs should be adjusting their false positive rate but they are steadfast in stating that it is 2% since the original sensitivity was 98%. This seems a little too neat and tidy for me. Why don’t the labs have positive predictive value rates which would give a much better indication of the chances of a positive being a true positive?

    • In response to your last question, why don’t the NIPS labs report a positive predictive value, I wish I knew the answer to that one, too.

      • Well, for a couple reasons.
        First, positive predictive value is actually kind of hard to understand. Many clinicians are not entirely clear on what PPV and NPV actually mean so the average patient is even less likely to do so. This makes it a very bad statistic in advertising speak because advertising does not do complicated. “Accuracy” is a very common concept that people latch on to.
        Second, the PPV for NIPS in low-risk populations sucks. Basically if you are already high risk, say a 1/10 risk of an affected pregnancy, then NIPT is 98% likely to detect an affected pregnancy correctly. However, if you are lower risk, say 1/1000, then the PPV is 32%. At 1/10000, it is 4%. (http://www.ajog.org/article/S0002-9378(14)02492-2/abstract. It’s behind a paywall I’m afraid.) This makes sense scientifically, NIPS cannot find what is not there, but is not the kind of thing that a for-profit company with investors really wants to spread around.
        The issue with Turner syndrome has been one of the worst, in terms of false positives. Some providers have reported that every high risk Turner result from NIPS has thus far been a false positive. The other interesting case has been findings of maternal abnormal karyotype. Because the clinical profile of Turner syndrome can be very mild, some women are completely unaware that they may be classified as monosomy. You can imagine the counseling for that one.
        Basically, MCBLINKIE, because it’s bad for business and they have no legal obligation to do so. If the FDA follows through on regulating laboratory developed tests this may change but at the moment, they can basically say what they want.

  9. Interesting article! Please allow me to share my story. I am hoping that I can help save other women from what I went through.

    Just in case you are all wondering: My husband and I are well educated with career backgrounds in the clinical laboratory sciences. I am a professor with a PhD in science. However, when you’re the patient, things are a bit different..

    I was pregnant in 2012 at age 37 due to give birth in 2013 at age 38. The results of my quad screen was a 1:10 risk/ probability of my baby girl having Downs Syndrome. I was strongly advised by my OB that I needed to get tested because of my age. We also had a Level II ultrasound to check for any early signs of DS – none were found. After both results, we were seen by the Genetics Counselor who, for lack of a better description, put the fear of God in both my husband and me. She was for sure that the baby will have DS. We were pushed to have the MaterniT-21 test — we politely refused. For each and every single visit to the OB we were reminded that our baby will most likely have DS and we needed to do this blood test or the Sequenom one. We kept refusing.

    Our OB (from a reputable teaching hospital in Los Angeles) insisted that my baby’s head was too small (at 5% range) and she was for sure that this is an indication of DS or a genetic disorder and she had to induce my labor. Because of the 1:10 screen, we leaned towards the strong possibility that the baby will have a genetic disorder and most likely DS. She was sure that we needed to induce to save the baby’s life as she was no longer growing appropriately in the womb.

    We listened to her advice and went through with the induction (even though I was only a few days late and got to the hospital 2cm dilated already).

    Long story short, I suffered placental abruption (which I suspect is because of the overdose of pitocin) as they kept telling me that the baby had IUGR or intrauterine growth restriction. I underwent emergency C-section, lost almost all of my blood, went into what I think were early stages of DIC (in laymen’s terms some say this stands for Death is Coming) or disseminated intravascular coagulation, and was transfused with at 8 bags of packed RBCs.

    My baby? She’s a beautiful baby girl, 6 lbs, 12 oz, 21″ long, a beautiful head, and no Down Syndrome. I was in the ICU for 3 days and only got to see text message photos of her. But I am a happy mom! She is now 16 months and I am grateful to be alive. Grateful for my surgeon who saved my life and my uterus!

    Am I angry? You betcha! But my focus is on the gratefulness that I am alive. I am compelled to share my story because I am wondering if I can help other women make decisions about these types of tests. I worried my ENTIRE pregnancy that something was wrong with my baby. I owe all of this worrying to my wonderful medical team (you should sense the sarcasm).

    • Thank you for sharing your story, Lane. I’m glad your daughter and you are both doing well. Your experience supports this study’s finding that too many medical professionals are administering prenatal testing incorrectly.

      • Thank you so much for allowing me to share my story. I hope that other women do the research about these tests and be vigilant about “firing” medical professionals who administer these types of testing incorrectly. We need to be educated consumers. Thank you for this article as well.

  10. Thank you all for your comments, this is very helpful.

    I am a little panicked right now and read a ton of information but still don’t know what to do. I am 13 weeks and 39 years old with my 3rd pregnancy. My doctor pushed Maternit21 at our first visit. I struggled for over a week and then decided to proceed with the NT test as usual. My first pregnancy I was 36 so I was already high risk by age but had beautiful numbers coming back, that of a 20 something year old so I was not concerned this time. However I got the call last week, the scan showed a “slight” because the doctor kept emphasizing that increase in the neck 2.4 and my results were 1:36 for downs only. The other tri’s came back with results of that of a 19 year old. I had a bad sinus infection and was sick when I took the tests. I also had a possibility of a UTI since my urine test came back compromised? I was assured that infection in my system would not alter the tests. Do you know if it would?

    Anyway my doctor said I already wrote the lab work up, come and pick it up and go take the Maternit21 test, my lab just started offering it so no need to go to a genetics counsler. I got up and ran to the doctor’s office shaking the whole way. I didn’t even think about it. If I did maybe I would have said no schedule a CVS now. I think I’m too late to take it and have to wait for an amnio?

    I took the test on Friday and am still waiting for my results. My doctor said although it is a screening test it will be close to positive tell me if the baby has downs and we can trust it. However this was weird, I said what if we get a positive result and I don’t want to proceed with this pregnancy, he said well then I would suggest you go to a genetics counsler to help you understand the results bettter. What? That confused me, wouldn’t he trust and understand the results. He just told me it would be very close to being right? I’m not saying I would terminate, I just wanted to see what the options were.

    Is this true? What can I expect to get back? I’m torn because I do respect and think my doctor is great but I don’t feel comfortable with any of this. I’m not sure if I should still do an amnio, I think I am too late for a CVS.

    Thank you for letting me vent and any thoughts you have would be helpful.

    • As this post explains, MaterniT21 and all the other tests like it, remain screening tests, with false positives and false negatives. Given your age, a screen-positive result from MaterniT21 would likely mean you had close to a 90% chance for having a child with Down syndrome–but that means you would have 10% chance of not having a child with Down syndrome (see this post here). Before making any decision to terminate, professional guidelines and medical ethics instructs that you should confirm your screening test with a diagnostic test. You are beyond the window for CVS, but can have an amnio after 15 weeks. I hope this helps, and I agree with your OB, that ultimately, you should meet with your genetic counselor to discuss this further.

  11. Dear doctor Leach, I am an expecting mother, AMA, I will be 40 at child birth. Do you know if a Maternit21 Plus taken at 10w+1 is just as reliable (having clear that we talk about odds, and not positive/negative results) as the same taken at, say 11 w?
    These few days may make a big difference to me.
    I’m Italian and live in Italy. Blood samples are shipped to California it takes 3 calendar weeks to get results. While I wait for Maternit21 Plus, I will of course get NT scan and, if such scan is worrying, will opt for CVS without further waiting. However, if NT is borderline Maternit21 may eìbe very relevant in deciding about invasive tests. Given the long time needed to get the results back in Italy I’d rather go for Maternit21 sooner than later, however, only if the exam is still reliable.
    Thank you very much for your excellent website.

    • Claudia–Sequenom’s website says its test is “indicated for use as early as 10 weeks gestation.” However, the later any NIPS test is done in a pregnancy, the more accurate it is, due to more DNA from the pregnancy being present in the mother’s blood stream. That said, if you’re AMA, then a screen-positive result from MaterniT21 would mean more likely than not you’re having a child with Down syndrome (or one of the other conditions the screen tests for) (see the chart at this post for the positive predictive value of NIPS tests). A correction and an appreciation: I am a lawyer with a master’s in bioethics, but I am not a doctor; and, thank you for your compliment of the website–I’m glad you found it helpful.

  12. This just happened to me but with the nurse at the drs office.. I wish she would have rephrased it because now I have to wait for my ultrasound tomorrow.

  13. I have a question, some one please answer. I am 31 weeks pregnant and 26 years old. I did the Marternity21 test because at one of my ultrasounds it showed my baby girl has only 2 vessels. Other than the two vessel cords all of the scans have been normal and they do not see any abnormalities. I got a call 8 days after taking the m21 and was told that my baby has turners syndrome, and did I want an amino, I said no, if it is in fact turners or any other syndrome I’m still keeping and having my baby, but now I am very stressed out.

    • If you were told that your baby had Turner syndrome based just on a MaterniT21 result, then that is incorrect. MaterniT21 and any other NIPS test is not diagnostic–they can not say for certain whether your child has a condition or not, only whether you have an increased chance for your child having that condition. Given your age, a screen-positive result would still mean more likely than not that your child does not have Turner syndrome. Further, the professional medical organizations do not recognize MaterniT21 or the other NIPS tests as valid for testing for sex conditions, like Turner syndrome. I would ask for a referral to a genetic counselor if you would like to discuss this further with a medical professional.

      • Sir, thank you for both the informative article and for your advice. I have been researching alot and alot of women have been getting false positives. The way the results were given to me, left me speech less and now have me stressing but thank you for the reassurance that everything could possibly turn out okay.I am due January 26th but have a history of preterm labor (last baby was born at 35 weeks) but I will definitely be back to inform you about how everything turned out for me.

        • what ever did happen for you? Im currently going through the something right now.

          • I meant to update. So I had my daughter genetically tested once she was born last month and although I haven’t officially spoken to a genetic specialist, I was told by my Ob that my daughter has what is called mosaic turners. Because they seen normal and abnormal cells. I am still waiting in the referral to the genetic counselor to find out more About her results. So far my baby looks like a normal infant, I’m so nervous.

  14. hi, i’m 44 years old but am pregnant with a 23-year-old donor egg. Does that put me in the category of high-risk 44 or low risk 23?

    • I would think low risk 23, since the “risk” concerns the chromosomes in the egg. I believe some of the labs do not, or have difficulty or lower accuracy, with donor eggs. I would ask your obstetrician, genetic counselor, or maternal-fetal medicine specialist.

  15. Hi I just received results from my M21 testing delivered to me as only negative.The test somewhat put me at ease I will be 24 when I deliver so my age is not high risk. However, I am considered high risk due to a second trimester miscarriage earlier this year with no definitive conclusion or results showing why. Knowing now the way the test actually shows results (it was not explained to me this way) I am going back, and forth with opting for an amino. My last ultrasound showed no physical abnormalities or developmental issues, but my baby has an excess amount of fluid around the heart “most likely” to be in normal range…I don’t like those terms, and an EIF in the heart that is not only associated with heart dysfunction but also Trisomy 21. I am scared to harm my baby going on a fishing expedition for what might not be there but I am also nervous about the false neg/pos results these test provide. Thank you for your time

    • Kristen–As discussed at this post, based on your age, you have a very low chance for having a child with Down syndrome. The MaterniT21 result confirmed this low chance, i.e. meaning your chance of having a child with Down syndrome is very low. We are finding more and more women are relying on MaterniT21’s negative report and avoiding the risk of miscarriage with an amnio. However, if you have to know for certain, an amnio is the diagnostic test. I would encourage you to discuss your concerns with your Maternal-Fetal Medicine specialist or genetic counselor, hoping you have been referred to these specialists. I wish you well with your pregnancy.

      • Thank you Mr. Leach, and yes I will be meeting with a specialist next week to further discuss the screening test results. I will then make known any further testing I desire, and hope for the best. Thank you

      • Hi, I am 39 years old and have 6 healthy children, ages 23-9. I am currently 15 weeks pregnant and had the MaterniT21 test performed during my 13th week. Well, three days ago my doctor called and said he had bad news, that my test results showed my baby has Trisomy 18. I asked if he was sure, and he said the test was 99% accurate. It has always been explained to me that this test is 698% or 99.9% accurate. Now I really don’t know what to do. I have never had a problem pregnancy, and I don’t FEEL like there is anything wrong. I am terrified of having an amnio, partly because I am afraid it will be positive, or it will be negative and I will miscarry. Is there anything that can tell me the risk factor now that my child has this awful condition? Do my results automatically mean I have no chance at having a healthy baby?

        • Tanya–Your doctor is repeating the often misunderstood accuracy rate for MaterniT21 and tests like it. This was the subject of a report just this past Sunday on how false positives remain. I wrote about the report at this post. Also, at a medical conference this year, at one clinic, a screen positive for Trisomy 18 meant more than likely the mom was not having a child with Trisomy 18 (see this post and poster 601). Because MaterniT21 and tests like it are testing DNA passed from the placenta, some theorize that the false positives for Trisomy 18 are due to placental mosaicism of Trisomy 18–where some of the cells of the placenta have Trisomy 18 but not the fetus. According to the Trisomy 18 Foundation, the incidence rate for Trisomy 18 is 1/2,500. Based on a Bayesian analysis (something a genetic counselor could do for you), a 99% accuracy rate really translates into only a 40% chance of having a child with Trisomy 18 (more on this analysis at this post). All this being said, per the guidelines, you should be referred to a genetic counselor to discuss these test results and receive the contact information for the Trisomy 18 Foundation, which can provide you the accurate information on what having a child with Trisomy 18 can mean. Then you can make your decision on whether it is worth risking a miscarriage in order to have a diagnosis from an amnio. I hope you receive the information and support you deserve.

  16. stephanie williams says:

    Thanks for posting this article. I am 30 years old with my first pregnancy at 18 weeks. Yesterday my OB informed me that I had a “positive” quad screen with 1:136 odds for Downs Syndrome. He is sending me for a level 2 ultrasound in a few days. After reading that u/s is not an effective screening tool for Downs, I called and requested the MaterniT21 this morning, awaiting a call back. If the MaterniT21 is “negative” or at least reassuringly low risk level, how necessary would an amnio be? I do not desire to have invasive testing, but who wouldn’t want to know for certain that things are ok? (as “certain” as possible, that is). It is my hope that the u/s coupled with a low MateriT21 will be enough to move forward with this pregnancy without fear.

    • As this article covers, screening tests, be it the quad or the MaterniT21 test, have false positives and false negatives. So, a “screen-negative” is never a true negative. That said, MaterniT21 and tests like it have very low false negatives. More and more women are opting to rely on a screen-negative MaterniT21 and avoid the risk of miscarriage from an amnio. If, however, you must know for certain, then an amnio is the diagnostic test. Professional medical guidelines recommend that you be offered genetic counseling, provided accurate written information about Down syndrome, and the contact information for your local support organization. Fear is largely fear of the unknown and by talking with your genetic counselor, reading about what a life with Down syndrome can be like, and meeting a fellow parent, perhaps your fear will diminish. That said, you still have a relatively low chance for having a child with Down syndrome based on your age and the quad test. I hope you get the information and reassurance you are seeking. More information on accurate information and support resources about Down syndrome can be accessed at the Prenatal Resources tab.

      • Thank you so much for your reply. I will be meeting with a genetic counselor after the U/S and can opt for MaterniT21 at that time. Once again, the OB is stopping short of calling the test diagnostic, saying “it’s a pretty diagnostic test, like 99.9% accurate”. Your article helped me look at this a little more critically. Thanks Mark.

        • Stephanie–I’m glad you’re getting the support you need. So disturbing though that the OB said “pretty diagnostic” and “like 99.9% accurate.” Neither statement even exists factually, i.e. there is no such thing as “pretty diagnostic,” it either is or it isn’t and the 99.9% is the specificity rate, but not the predictive value. See my comment to Tanya above and the links to the posts there which discuss this in greater detail. I wish you well with your pregnancy.

          • Dear Dr. Leach,
            I did NIPT Illumina test and receive positive result for Trisomy 18. I am wondering if you know about the accuracy of this test.

          • Rosie–each non-invasive prenatal screening (NIPS) laboratory claims very high rates for their tests, including Illumina. However, those high rates pertain to their tests’ ability to detect a pregnancy carrying a fetus with the tested-for condition. All of these conditions, trisomy 18 included, are rare conditions. Therefore, there remain false positives and in the case of rarer conditions like Trisomy 18, even with a high rate of detecting affected pregnancies, the tests still report false positives such that a “positive” with a 99% accuracy rate can really only mean a 50/50 or lower chance. In the case of Trisomy 18, false positives have been reported at such a high rate that the practices are changing how they counsel their patients, to ensure they understand it could be a false positive. See poster 421 at this blog post of mine. Professional guidelines recommend that you see a genetic counselor to further explain these results and to refer to the parent support organization for the tested-for condition–for Trisomy 18, one of the organizations is the Trisomy 18 Foundation. I hope this is helpful and that you receive the support and information you deserve. One last post-script, while I have a Juris Doctorate, that makes me a lawyer, not a medical doctor.

          • Dear Mr. Leach,
            Thank you so much for your reply. The info is very helpful. I will hope for the best and prepare for the worst.

          • stephanie williams says:

            Just an update – I opted to have the amnio. Preliminary report and final were all good news. Still awaiting the targeted assay. I appreciate your fast answers to all our questions and comments.

          • Stephanie–thank you for sharing your results. Can you clarify: did you ultimately have the MaterniT21 prior to the amnio?

  17. My maternit21 test came back positive for trisomy 21. I declined an amnio because I will find out at birth either way. I have spent months looking on line for false positive cases. I have only found 1 and have seen hundreds of confirmed cases. That being said it seems to be at least 99% accurate. Is there something I am missing? I hope my test is wrong but I don’t see much hope.

    • Sarah–more and more women are making the choice you have made: to rely on the non-invasive prenatal screening (NIPS) result, in your case MaterniT21, forgo the risk of miscarriage with an amnio, prepare for having a child with Down syndrome, but knowing there’s a possibility of being surprised at birth that MaterniT21 was a false positive. In this series of posts (linked here, here, and here), I covered how the claimed 99% accuracy rate never reaches that high for actually predicting the chances of having a child with Down syndrome. I hope those posts are helpful.
      Having received a screen positive result, professional guidelines recommend you receive genetic counseling to better understand the results, be provided accurate written information, and receive the contact information for your local support organization. The prenatal resources tab (linked here) has the written information approved by the most recent statement on NIPS and links for locating your local support organization. I hope you find those resources helpful as well.

  18. Hello Mark,

    My Panorama screen at 9w6d came back low risk. The OB did not recommend an NT scan, therefore I did not have one. My 16 week ultrasound showed no signs of chromosomal abnormalities. My AFP alone (not the quad) done at 17.9 weeks came back negative. Does a low AFP indicate down syndrome? Although all screens show a low risk or negative, I am still a little nervous due to my age of 38 (will be 39 when I deliver) and that I may have a false negative. I am still considering an amnio but I am scared of the miscarriage risks. I have my 20week ultrasound tomorrow and hoping that will also show no markers. With all my screens being low risk or negative, do you think an amnio is necessary? Why do false negatives occur with the NIPT?

    Amy

    • Amy–False negatives can occur with NIPT for a number of reasons: the tested material was not from the fetus, there was a lab error, there was an insufficient amount of fetal material to be tested. Regardless, it sounds like every screen you have had suggests a low probability of having a child with Down syndrome, which confirms your baseline low chance from just your age (around 99% chance of NOT having a child with Down syndrome). The false negatives with NIPT are more rare than the false positives. Many women are choosing to rely on a screen-negative from NIPT and avoid the chance of miscarriage. Professional guidelines recommend that you receive genetic counseling following your NIPT. Given your multiple screens, I would be curious if a genetic counselor could give a more sophisticated analysis of what all your results mean. That may give you the confidence to rely on the NIPT result and decide the chance of miscarriage isn’t worth the confirmation an amnio could provide. I hope you receive the support and advice you should get.–Mark

      • Thanks for your response Mark. I did speak with a genetic counselor after my 16th week ultrasound, and she laid out the risks of the amnio vs. the low risk of the panorama screen. However, as I am at the halfway mark (20 weeks), I am getting more anxious of the false negative. My fetal fraction was 5.3% and since it was taken before 10 weeks, I am a little apprehensive if the fetal fraction was enough for an accurate result. My OB thinks that an amnio is unnecessary at this point. My 20th week ultrasound appointment showed no signs of abnormalities today so it is a good sign.

        • Amy–“necessary” is a value-driven term in this context. From the beginning of your pregnancy, the only way to know for certain about your fetuses genetic make-up was through either a CVS or amnio, with both risking a miscarriage. So, the screening tests have been done to reassess your likelihood. Every test has come back as unlikely that your pregnancy is affected by a genetic condition. That said, while I doubt it would be reimbursed by insurance, you could pay out of pocket for another NIPS test. The later NIPS is performed in a pregnancy, the more accurate it can be due to more fetal DNA entering the mother’s bloodstream as the pregnancy progresses. I’m not sure that option has been discussed with you. If you do choose to have a another NIPS test, that may give you the reassurance you are seeking, since it would be unlikely to have two false negatives (particularly given it’s unlikely to have a single false negative). I hope this helps.

  19. My sister-in-law is 41 and was just told she received a positive result for Trisomy 18 using the Materni21 test. Her doctor is recommending she undergo amniocentesis to confirm. I have heard you reference the risks of miscarriage from amniocentesis. Do you have any information on how high that risk is? She is really torn. To me, it seems like inviting a very real risk through amniocentesis would be worse than the probabilities associated with these screening tests. So, any information you have on the risks of amniocentesis would be helpful. I do not know her probability or percentage for the Trisomy 18 screening result from the MaterniT test but could probably find out if you think that would influence your response. Thank you.

    • Nicole–the risk for amniocentesis was historically quoted as 1% but in the early 2000’s, a couple of hospitals published studies showing their risk was around 0.7% or lower. The only percentages that matter are the following two: the rate of miscarriage of the specific provider performing the procedure and the rate at the facility where the procedure will be performed. It doesn’t matter if a hospital in St. Louis has a 0.7% miscarriage if your sister-in-law will be at a hospital in Toledo with a 1.8% risk. So, I would have her ask her doctor for his or her rate and the facility’s rate of miscarriage. They likely don’t keep hard data on that, but her doctor should be able to report what his or her own experience has been. I would also have your sister-in-law have her doctor specifically ask Sequenom (the maker of MaterniT21) what her positive predictive value is. If she is told her result means she really has only a 1 in 200 chance of having a child with T21, then she may decide the risk of miscarriage is greater than her risk for having a child with T18 and opt to skip the amnio. At this post are several comments from women getting a screen positive for Trisomy 18 and my responses with links to studies finding false positives happening with Trisomy 18 results. I hope this helps.

      • Sir, thank you so very much for this information. This is exactly what I needed to help her make an informed decision. It is greatly appreciated. Will let you know how it all turns out.

  20. Hi I’m 19 years old and 25weeks pregnant,I did the MaterniT21 and tested positive for trisomy 21 the MSAFP test I did at the begging of my pregnancy was negative for down syndrome but why is this test now positive could this test be wrong I’m to scared to have the amino test done because of the risk, please help I’m a reck

    • Professional guidelines recognize NIPS tests like MaterniT21 as only being accurate in what are considered “high risk” pregnancies. Given your age and screen-negative AFP result, I’m not sure why you were offered the MaterniT21 test. That said, based on your age and with your MaterniT21 result, at best, it means you only have a 40% chance of having a child with Down syndrome–meaning it is more likely than not that you are not carrying a child with Down syndrome (see this post here for more on this). But, the only way to know for certain is with an amnio. I would ask to speak with a genetic counselor to both further discuss your prenatal screening results and so you can make an informed decision about whether you will have an amnio. Having received a screen-positive NIPS result, per the American College of Medical Genetics & Genomics guidelines, you also should have been given a copy of the Lettercase booklet and referred to brightertomorrows.com to learn more about Down syndrome. You can find links to those resources at the Prenatal Resources Tab. Consider this information as well when deciding whether to have an amnio. I wish you well.

      • Hi Jahmeila. First, it is important to stay calm. As Mark (and lots of other people) have repeatedly said, MaterniT21 is just a screen. It doesn’t actually tell you anything for sure, just a suggestion one way or another. The only way to know for sure is to do a diagnostic test like amnio. You should talk to your doctor, but understand that in a large American hospital the ‘risk’ of amnio is very, very, very small. It is considered a completely routine procedure which very rarely has any side effects, let alone a miscarriage. Given your age, if you feel that you need definitive information either way, the amnio is the only way to get it. The only question is whether you feel like you, personally, absolutely need to know one way or another. This is something a genetic counselor can help you think through. The biggest question is whether the information is useful to you in some way. If you think you would consider termination, this information might be relevant. If you would not, some people still find the information useful to help them prepare for the changes in their life going forward. But some people don’t find the information useful at all since they wouldn’t change anything whether the answer was yes or no. So it really comes down to you and your personal needs.

  21. BE Informed says:

    A diagnosis of Down syndrome tells you NOTHING about the prognosis of a LIFE. People with DS live, long, healthy productive AMAZING LIVES.

    There is NO medical or other complication that is untreatable and particular to DS. People are treated and helped for conditions that babies with DS have.

    Please educate, not terminate.

  22. 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.

    • catherine says:

      Hi… I received my harmony test results a few days ago and I am now waiting to have an aminocentesis. The results of the harmony read low risk (less than 1/10,000) for T21, T18 & T13. We are having a boy but the sex chromosome analysis shows a probability of 2/100 = 2% for XXY Klinefelters syndrome. Is the presence of XXY at any % of probability a positive? or is this level of detection being 2% risk anything to worry about? I can’t seem to find much information about intermediate results like mine, just on the high or low ends of the scale..

      Thank you in advance

      Catherine

      • There is little known about the accuracy of NIPS like Harmony for sex chromosomal conditions. So little that the professional organizations do not recognize NIPS as being valid for screening for those conditions. Coincidentally, I’m at a genetics conference and research by Kaiser Permanente found that more often than not a NIPS result for a sex chromosomal condition meant the child did not actually have the condition. I hope your amnio went well.

  23. Hi. I’m 35 years old and had the MaterniT21 done at 11 weeks. My OB called me this past Thursday (a week after the test was sent off) and told me that my test came back positive and my baby will have Down Syndrome. She said the test is pretty accurate and has referred me to a genetic counselor. I was not told that this is a screening test. I was told my baby will have Down Syndrome. This is my first child and there is no family history that I know of (I don’t know if that makes a difference). Your article has given me some hope but I truly don’t know what to think.

    • Your OB is mistaken. See the graph at this post. Given the baseline chance from your age, a “screen-positive” results from a test like MaterniT21 means you have around a 75% chance of having a child with Down sydnrome and a 25% chance of a false positive–but that is a pretty significant chance of a false positive, i.e. 1-in-4. I would share this fact sheet about tests like MaterniT21 with your OB which explains they are screening tests. Being referred to a genetic counselor is consistent with professional guidelines and hopefully you’ll get better advice and information from her. Per the guidelines of ACMG, you should also receive the Lettercase booklet and brightertomorrows.org is another resource identified by ACMG for moms receiving a test result for Down syndrome. I hope you find those resources helpful and that your OB learns more about NIPS tests like MaterniT21.

      • Thank you so much for your reply. The information you and your site provided had been extremely helpful. I feel a little more at ease but Friday feels like an eternity away to see the genetic counselor.

        • No doubt it does. Many moms are finding help through on-line support. One such on-site group is the Downsyndromepregnancy board at babycenter (much of the wisdom in Diagnosis to Delivery is from what the moderators of this board learned). There are other boards at babycenter concerning prenatal test results. I cannot vouch for any of the other boards, but know that the Downsyndromepregnancy board is responsibly moderated.

        • Kundra, I had a similar experience in early March. We were told our little girl has a heart defect and because of my age she will have DS. Then we went home and found out not all CAVCD babies have DS. So then we were told that we could take a new test that was 99.9 accurate. We had declined amnio. We took the test and it came back positive for T21. I was never told it was a screening. I recently explained to my doctor that I have come across numerous parents who have gotten false positive results. Much more for T13/T18 & Turners but the T21 false positives are not rare. I reached out to a mom who recently posted in a DS facebook group that her little girl came early and tests confirmed that her free cell dna test was a false positive. Her little girl has no chromosomal abnormalities. Like myself, she reached out to the DS community under the impression it was a diagnosis. I asked her which test but she didn’t know she only said free cell DNA and her little girl was still in the hospital so I didn’t want to keep bothering her. Our most recent heart specialist updated us on our daughters condition and said that she was aware that there was a strong possibility of DS with the heart defect and Panorama test but without amnio we wouldn’t be sure until birth. We would have the test done at that time. I wish we would have her first. She was very compassionate and obviously didn’t regard our Panorama test as a diagnosis. If our results end up being a false positive, I think ours will be the only one with a heart defect. We find more comfort each day with our little girl having DS. I am still shocked at what I am finding. Not only that but when parents reach out looking for information on Baby Center posts regarding free cell DNA accuracy my posts get deleted and one group owner sent me a private message to stop posting links to articles and other feeds having the same discussion. One lady vented that she thought the test reps were trolling the posts. I have relied on Mark’s links and have read everything I can get my hands on but there is no shortage of false positives. You are not alone. Our genetic counselor was awful. I was also told by a local midwife that they don’t encourage the test because women are terminating for GENDER results from free cell DNA. Best to you! I am trying my hardest to enjoy this pregnancy but I still cry a lot. I am terrified of loosing her.

  24. Hi. I’m 41 years old and 14 weeks pregnant. I had NT at 12weeks and my ultrasound doctor said that everything looked good. I had the MaterniT21 Plus after the NT due to the concern of my age and previous 3 consecutive miscarriage (my first child is healthy, and 7 year-old now). I got the MaterniT21 result yesterday, showing positive for trisomy 21. I was very scared and asked for my risk score but my counsellor said that it was not available, only positive or negative. I understand that the test sensitivity for trisomy 21 is 99.1%. Your article has given me some hope but I truly don’t know what to think. Given my age, what could be my chance of carrying a baby with Down syndrome, do you know?

    I will have amniocentesis next week (when I am at 14 weeks and 5 days). My counsellor said that I will know the primary result of the amnio test after 3 days (and she said many people used this primary results to make decisions on their pregnancy), and the final results will be available after 2 weeks. Do you know if the primary result of the amnio test is conclusive enough to make decision?

    Thank you.

    • Jenny–I’m concerned about the advice you’ve been given. The American College of Obstetricians & Gynecologists (ACOG) practice guidelines for screening tests say a screen result should be reported as a positive predictive value, i.e. what you referred to as a “risk score.” From the chart at this post, your positive predictive value is around a 7.5% chance of a false positive and a 92.5% chance that your child has Down syndrome, based on your age and the MaterniT21 results. The information you’ve given about diagnostic testing is concerning. ACOG does not recommend an amnio before the 15th week, yet you are scheduled 2 days before the 15th week. Also, the preliminary results, known as FISH, is not the full test and does not test as many cells as the full amnio. The only way to know for sure is to wait for the full results. I would recommend getting a second opinion. Further, per the ACMG guidelines, you should have received information about Down syndrome with your MaterniT21 results. Those resources are the Lettercase book, Understanding a Down syndrome Diagnosis (available on-line and in hard copy), brightertomorrows.org, a website with information about Down syndrome, and the AAP healthcare guidelines for individuals with Down syndrome. I hope those resources are helpful to you.

      • Thank you so much for your reply. The information you and your site provided is very helpful. I will check the links you suggested. My counsellor did not give me any information about Down syndrome. She just called me to inform that the test is positive with T21 and recommended me to re-schedule the amnio test earlier (originally, she scheduled it for me at my 15weeks and 2 days). I checked with my OB doc. about this change, she said if the result of the amnio would change our decision on the pregnancy, then do it sooner is better. I felt not at ease with their recommendations, and am very glad to find your site.

  25. catherine says:

    Hi Mark,

    I originally posted on March 27th, at thst time I awaited an amniocentesis procedure as I received an abnormal Harmony test result. (XXY detected PPV 2%, low risk for T21, T18, T13). We received a normal amniocentesis result, so just to give hope to anyone else that received abnormal sex chromosome results via Harmony test, Mark you replied to my post and said that this screening is not accurate for sex chromosome conditions, you were right and thank you for your words of wisdom that kept us sane whilst we awaited the results of our amnio. I wish you all well.

    Thank you

    Catherine

  26. Cheryl says:

    I’m 39 and expecting my second child. I had an NT scan and blood draw for MaterniT21 at 13 weeks, 3 days. The NT measured 2.9 and the perinatalogist told me there was a 1:75 chance of a possible heart defect based on the measurement. I met with a genetic counselor to go over family history and discuss the NIPT options. A few days later I get a call from the GC saying my M21 test came back positive for T21 and that false positives are extremely rare. Needless to say, I was really shocked. No warning, just bam, your baby has downs syndrome. The GC asked if I even wanted to know the gender and said she was really sorry. I’ve been doing a ton of research looking for hope, but getting very mixed information. I have an amino scheduled, but feeling pretty hopeless. I am a scientist and know a little about statistics, so just want to know what a positive M21 result really means. Thanks!

    • Cheryl–See the graph on NIPS PPV at this post. Based on your age, a screen positive with MaterniT21 would mean you have approximately a 90% chance of having a child with Down syndrome and a 10% chance of a false positive. It sounds like your GC is unaware of these helpful resources published this year by the National Society of Genetic Counselors: a fact sheet on NIPS and a fact sheet on Down syndrome. Per guidelines of the American College of Medical Genetics, you should have also received a copy of the Lettercase book, Understanding a Down Syndrome Diagnosis, and you can find helpful information at brightertomorrows.org. I hope these resources and information are helpful.

      • Cheryl says:

        Thank you for the response. Still not great odds, but better than the 99% I was originally told. I did not get any resources from my genetic counselor, so I will review the ones you listed.

Trackbacks

  1. […] tests, NIPS, most of the labs do not report their test results in a 1-in-N format. Sequenom even touts as though it’s a good thing that it reports a “positive” or […]

  2. […] in this practice’s experience, if you received a “positive” NIPS (which there is no such thing), you actually had a 75% chance for a false […]

  3. […] accurate as NIPS may be, it remains a screening test and never definitively detects a chromosomal condition. And, the method of preventing the birth of children […]

  4. […] and does not have the diagnostic accuracy of amniocentesis.  By its very nature, a screening test does not tell with 100% certainty whether or not a fetus will be affected by a given disorder. Unfortunately, in […]

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