Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity studyBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.c7401 (Published 11 January 2011) Cite this as: BMJ 2011;342:c7401
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Re: Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study
Dear Prof. Nicolaides,
Each year, the 21st of March is celebrated as “World Down’s Syndrome Day”, in this context I am writing to you regarding a few concerns I have about the new prenatal screening blood test that is currently being piloted by yourself for possible inclusion within the NHS. I am neither a pro-life campaigner nor a social activist, I am writing to you as a mother - a mother of a child with Down’s Syndrome.
My daughter is five years old and she has Down’s Syndrome. Although I was scanned and monitored regularly during my pregnancy we were not aware that she had Trisomy 21 until after she was born. Before I went in for my first prenatal-check-up, my husband and I had talked about what we would do if we were told that our child had a chromosomal/physical anomaly, and in our naivety we had smugly decided that we would never ever think of termination. I now often wonder how we would have reacted had we known prenatally that our daughter had Down’s Syndrome - the chances are that despite our resolve and determination, we may have terminated the pregnancy purely due to the lack of awareness of what exactly it meant to have a child with Down’s Syndrome. As mental health professionals, both my husband and myself had been exposed to a very different side of lives of people with Down’s Syndrome, mostly restricted to those institutionalized who had co-morbid psychiatric illnesses and/or major behavioral disturbances (which no doubt would have cast a shadow on any decision that we may have had to make, had we known prenatally). But now, our perceptions have undergone a change - a change brought about by having been parents to our five year old daughter. From the moment she was born, one look into our daughter’s eyes (yes, those very ‘almond shaped eyes’ as highlighted by the Registrar who told us about her diagnosis) gave us the message that “no child comes with a guarantee, I am your flesh and blood, a part of you, this is who I am, accept me as I am” - which is probably a message that every newborn seeks to send his/her parents. Becoming parents taught us to rescale our views, to re-evaluate the concept of ‘normality’ and to appreciate life in its true glory. Our daughter did have physical health issues, she did undergo the dreaded cardiac surgery, she does have developmental delays, but she is a well-rounded, well adjusted child who has a good quality of life. She attends a mainstream school (and copes well despite additional sessions of intensive speech and language therapy and physiotherapy), she has friends, she is popular, she has strong likes and dislikes (like any other 5 year old), she has a strong personality, she is a determined, persevering little girl (and equally stubborn and unyielding - again, like any other 5 year old). I can’t imagine our lives without her!
All I am trying to say is that while I congratulate you on developing and carrying forward this new non-invasive, highly accurate tool that can help in prenatal detection of trisomies and other chromosomal abnormalities, I am trying to voice my concern regarding its use (especially if it is going to be freely available as a part of the NHS prenatal screening program). As a researcher I can understand the importance of your work, however, as a parent I am concerned that without adequate precautions and preparations, such a tool may lead to devastating consequences if and when it permeates the clinical setting. Recent reports in the media have highlighted one of its uses to include “the eradication of Down’s Syndrome” and as a parent of a child with Down’s Syndrome, I cannot help but feel chagrined (I’m sure you’ll agree that a large percentage of positive detections end in terminations, as you know, there are statistics available that report this fact). This whole notion of ‘eradicating’ a set of people due to the presence of one extra chromosome sounds very similar to a pre-world war propaganda or the philosophy of Francis Galton. I am in no way insinuating that your research team is involved in voicing these views, but bringing to your attention how the public is being biased by popular media. While early detection has innumerable benefits (managing health needs, psychological preparation and putting resources in place being some of the main positives), if it occurs in a society where there is a lack of awareness - especially when the “detected condition” is viewed as a disability which is either stigmatized or that which causes a great deal of suffering- it could possibly prove more harmful than envisaged.
I am sure the rigorous scientific protocol of your study would ensure that the tests are carried out only when indicated and by trained professionals, but I am concerned about its introduction into mainstream NHS clinical settings without the background work that would ideally need addressing prior to its use. I am concerned that the test - if left in inexperienced hands may lead to biased disclosures, if the attitudes and prevailing beliefs remain unchanged, the positive test results would then lead to terminations of innocent lives.
I am concerned that my daughter may end up growing up in a society where she would be a very, very small minority (smaller than nature’s intended 1 in 1000).
Viba Pavan Kumar
Competing interests: No competing interests
This test does not replace nuchal screening or karyotyping, as it
does not give the same information as either test. It may be satisfactory
for low risk women who are only concerned about Down syndrome, but they
will only know they are low risk if they have first trimester combined
screening. In addition, they may only be concerned about Down syndrome
because they have not been informed about other chromosome abnormalities.
Down syndrome results on karyotyping, for women at increased risk of Down
syndrome after combined first trimester screening, comprise only about 50%
of the chromosome abnormalities detected for this referral group. The
clinical significance of these abnormalities are often questioned by
health professionals, however we don't know if pregnant women have the
The concept of a non invasive diagnostic test for Down syndrome is an
excellent one, but it's implementation will need to be very carefully
thought out to ensure that women are making informed decisions about the
type of testing they have.
Competing interests: No competing interests
This may not replace amniocentesis ,as there will be some parents
seeking absolute confirmation of Triosomy, but, if economically viable and
confirmed in wider populations, could replace other methods of estimation.
If I was amongst the patent holders , I would be thinking very hard
about the pricing.If I owned a nuchal scanning contract , I would be
looking at my small print.
Dennis Lo should be congratulated for his quarter-century pursuit of
Competing interests: Diploidy
Despite the importance and the advantages of the non-invasive
prenatal diagnosis, the risks of Amniocentesis and CVS are clearly and
surprisingly overestimated in the article of Chu RWK, et. al.(1)
The pregnancy loss rate after midtrimester amniocentesis has been usually
quoted to be approximately 0.5%. This risk was derived from three studies
in the United States (2), Canada (3), and Great Britain (4) performed in
the 1970s, who were performed in a time when ultrasound guidance for
amniocentesis was not routine, and the clarity of ultrasound in the 1970s
was relatively poor.
Chu RWK, et al give a risk of 1% quoting a study by Tabor A et al from
1986(5), this study had unexpectedly low background loss rate in the non-
amniocentesis group, and other concerns.
A 2006 study (6)with total of 35,003 unselected patients from the general
population with viable singleton pregnancies Patients who either did
(3,096) or did not (31,907) undergo midtrimester amniocentesis were
identified. They found evidence that the real added miscarriage risk of
amniocentesis is only be 0.06% -- which equates to 1 in 1,600.
miscarriages that occurred after an amniocentesis might not be
attributable to the procedure itself.
After that study, the Washington University School of Medicine analyzed
its own information from 1990 to 2006 and found that the increased risk of
miscarriage after an amniocentesis was only 0.13% -- 0.97% of women who
had an amniocentesis before 24 weeks had a spontaneous late miscarriage
or preterm birth, but this also happened in 0.84% of women who did not
have an amniocentesis. They concluded that the difference was not
Many obstetricians and geneticist agree that the traditionally quoted risk
of 0.5% for amniocentesis is an overestimate, but Non-invasive prenatal
assessment of aneuploidies will be a welcome development.
1. Chiu RWK, et al Non-invasive prenatal assessment of trisomy 21 by
multiplexed maternal plasma DNA sequencing: large scale validity study.BMJ
2. Midtrimester amniocentesis for prenatal diagnosis. Safety and accuracy.
3. Simpson NE, Dallaire L, Miller JR, Siminovich L, Hamerton JL, Miller J,
et al. Prenatal diagnosis of genetic disease in Canada: report of a
collaborative study. Can Med Assoc J 1976;115:739-48.
4. An assessment of the hazards of amniocentesis. Report to the Medical
Research Council by their Working Party on Amniocentesis. Br J Obstet
Gynaecol 1978;85 suppl:1-41.
5. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pedersen B.
Randomised controlled trial of genetic amniocentesis in 4606 low-risk
women. Lancet 1986;1:1287-93.
6. Eddleman KA, et. al. Pregnancy Loss Rates After Midtrimester
Amniocentesis. Obstetrics & Gynecology. 2006. 108,5,pp 1067-1072
7. Kuehn BM. Study Downgrades Amniocentesis Risk. JAMA. 2006;296(22):2663-
2664. doi: 10.1001/jama.296.22.2663
Competing interests: No competing interests