Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

In Genes, Genomic Medicine, Neuropsychology, Neuroscience on Wednesday, 26 September 2012 at 07:30

posting as an addition to my recent post on genomic medicine.  the growing field and research in genomic medicine raises some interesting ethical issues.

Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

Elizabeth H. Dorfman; Mildred Cho, PhD

Editor’s Note:
Technological advances have enabled researchers to sequence an entire fetal genome noninvasively by extracting cell-free fetal DNA from maternal plasma.[1,2] This use of noninvasive prenatal diagnosis (NIPD) shifts the focus away from screening for known or suspected anomalies and inherited conditions to potentially discovering a wide array of information about the fetus that patients and clinicians might not be prepared to address.

On behalf of Medscape, Elizabeth H. Dorfman, a graduate student at the University of Washington Institute for Public Health Genetics, Seattle, Washington, interviewed Mildred Cho, PhD, Professor at the Stanford Center for Biomedical Ethics, Stanford, California, about the ethical and social implications of NIPD and how advances in these techniques might affect clinical practice.

Ms. Dorfman: Let’s start with a few background questions to set the stage. Can you briefly describe the technique behind NIPD using cell-free fetal DNA?

Dr. Cho: NIPD allows prenatal testing to be done from a sample of maternal blood instead of having to take a sample through invasive techniques, such as amniocentesis or chorionic villus sampling. There are a lot of different ways of analyzing fetal DNA in maternal serum; this technology, which is more recently developed, enables one to look at fragments of cell-free fetal DNA as opposed to fetal cells in maternal blood.

Ms. Dorfman: In regard to the timing of testing, risk to the fetus or the pregnancy, or potential for incidental findings — are they substantively different for NIPD compared with existing tests, or are they similar?

Dr. Cho: NIPD could potentially be used earlier in gestation, so that would give people more time to think about what to do with the results. Right now, I don’t think it’s being used very early because the ability to get enough DNA in the sample hasn’t been worked out fully, but that is the hope. Obviously, because it’s noninvasive, that makes a big difference to the person who is giving the sample: Not only is it not uncomfortable or painful, but there is virtually no risk to the fetus from taking the sample.

Ms. Dorfman: A team at the University of Washington recently announced that they had used noninvasive cell-free fetal DNA methods to sequence the entire genome of a developing fetus.[1] Could you go into a little bit of detail about how this changes the scope of NIPD?

Dr. Cho: Currently, fetal testing is done either to screen for one of a small number of conditions, or as follow-up to a prior screening, such as a genetic screening or fetal ultrasonography. In these cases, the fetal diagnostic test will be used to focus on any conditions or anomalies that turned up positive in the prior screen, or to detect a condition that is of particular concern that may have been identified through a family history. So, diagnostic testing will be just that: diagnostic, trying to come up with a genetic cause for an observed or suspected anomaly.

When or if it becomes possible to do whole-genome analysis in a clinical setting routinely, it will open up the possibility that people can get information about the fetus that is well beyond a handful of known fetal conditions, such as a trisomy. This raises the concern that people will be faced with a huge amount of information about which there might be a lot of uncertainty and will have very little time to consider what to do with the information.

Thinking even further into the future, one of the concerns is that it could potentially change the way people think about pregnancy because it might be perceived that they have a lot of choices to make about what kind of children they want to have. Moving from a limited set of conditions to potentially any kind of human trait that has a major genetic component could really change the way people think about pregnancy and prenatal testing.

Ms. Dorfman: How does this potentially expanded capability reconcile with current practice guidelines and policy statements related to genetic testing in children? For example, the American Academy of Pediatrics Committee on Genetics’ recommendations on ethical issues with genetic testing in pediatrics,[3] or the National Society of Genetic Counselors’ position statements on prenatal and childhood testing for adult-onset disorders.[4]

Dr. Cho: There is going to have to be some further thought about how this kind of fetal testing might be used by clinicians. The current guidelines don’t really speak to whether there are professional limits on what clinicians will and will not use genetic testing for, so the clinical communities will have to ask themselves whether there are any genetic traits for which they won’t offer testing, or whether there are any limits on information that they will provide to patients.

Ms. Dorfman: As a follow-up to that, the editor’s summary of the University of Washington study that was published in Science Translational Medicine [1] stated, “An ideal prenatal genetic diagnostic would noninvasively screen for all Mendelian disorders early in pregnancy.” I was wondering whether you agreed with or had any comments about that statement.

Dr. Cho: We have to think about what “ideal” means to different people. We can currently test for a lot of mendelian conditions, and yet a lot of people don’t opt to get those tests. For a lot of people, that kind of information might be unwanted; some of it may be the kind of information that won’t have any bearing on how people treat their pregnancies, or it may not be relevant until after the child is born. I think that’s something that can be debated, whether that’s an ideal situation or not.

Ms. Dorfman: NIPD requires a blood sample from the pregnant woman, and as you have described, carries no risk for miscarriage or direct fetal harm. Of note, this has raised concerns about inadequate informed consent, and I was hoping that you can comment on where this concern came from.

Dr. Cho: People who are already familiar with prenatal screening tests that analyze maternal serum already know that sometimes, women may not realize that one of the blood samples taken during pregnancy was not used to check their blood glucose, but was actually a prenatal screening test. So I think the concern is that if there isn’t a specific and unique procedure that is part of the prenatal testing process, it could go almost unnoticed until the results come back — and then be a shock to people who get the results. They might not understand the implications of this type of testing.

Ms. Dorfman: Is there consensus about the information and risks that should be disclosed in the informed consent process before NIPD?

Dr. Cho: I don’t think there is consensus on how to deal with information that should be disclosed in almost any clinical situation, and no, I don’t think that there is consensus for how to deal with genomic results and NIPD.

Ms. Dorfman: What risks do you think should be disclosed before testing?

Dr. Cho: People should understand that a prenatal test is being done and that the information they might receive from that test could be very broad and potentially have a major impact on decision-making. And if they have a choice to not get all that information, they should understand that as well.

The consent process should note the risk for getting information that the person might not want, and also that the information might affect family members as well, who may not be interested in getting genomic information.

Ms. Dorfman: Noninvasive testing using cell-free fetal DNA can be used to determine fetal gender as early as 7 weeks’ gestation. Is there any reason to think that this will promote prenatal sex selection in regions where this has not been a problem or exacerbate the practice in regions where this is already a concern?

Ms. Cho: There might be reason to be concerned about the use of cell-free fetal DNA testing for sex selection, especially in areas where gender imbalance is already widespread. Even if there are laws against sex selection, it would be relatively easy to get a blood sample and also relatively easy to send it out of the country, and to get a result back.

It’s something to be aware of and keep tabs on. Companies that offer testing will have to think about how they’re going to determine whether the samples are being used for things that are actually illegal in other countries; it may be their obligation to ensure that they’re not contributing to illegal behavior.

Ms. Dorfman: The American College of Obstetrics and Gynecology has published a position statement that this new technology should not be used for the purposes of sex selection.[5] Do you have any recommendations on what, if anything, should be done proactively to prevent that from becoming an issue in such countries as the United States, where we don’t see this as an issue but where we also don’t have laws banning it?

Dr. Cho: There is a professional stance against sex testing in the United States. But in places where sex testing is not necessarily against professional guidelines or is illegal, there needs to be more thought about what responsibility the testing companies have and what practical measures laboratories can take to ensure that they’re not potentially violating the law.

Ms. Dorfman: There is significant interest in whether and when to return genetic results to patients. How does this take shape in NIPD?

Dr. Cho: This question of returning results of genomic findings may be even more important in prenatal testing than in other clinical situations. In prenatal settings, patients typically have very broad autonomy to make decisions about what kind of information they seek and about what kind of information they have access to. It’s a little different from returning results in, say, adult medicine where you could argue that genomic results shouldn’t be treated any differently from other kinds of medical testing. But in the prenatal setting, there is usually such a premium put on autonomy of the patient to make decisions about her pregnancy that it puts the issue of returning results in a bit of a different light.

Ms. Dorfman: Noninvasive methods that require both a maternal and a paternal sample to determine which of the DNA segments are from the fetus could introduce additional opportunities for incidental findings. Could you comment on that?

Dr. Cho: I agree; when you’re getting samples from the mother and the father, you definitely have a much greater potential for incidental findings. It should be part of the consent process and their understanding of what kind of results they may potentially get back.

Ms. Dorfman: What efforts are currently under way to characterize how NIPD is affecting clinical practice and reproductive decision-making, if any?

Dr. Cho: Some people are studying the clinical implementation of NIPD, which is currently limited to aneuploidy detection. I don’t know that it’s being studied broadly for applications other than aneuploidy at this point, but I imagine that will happen in the near future.

A side issue that might become influential in the application of cell-free fetal DNA research to clinical practice is the question of intellectual property and whether patents for cell-free fetal DNA testing might affect how clinicians can or cannot use the test. The ethical side of this is how or whether intellectual property policy should be allowed to dictate how clinical tests are or are not available to clinicians and patients.

Ms. Dorfman: Looking ahead, how do you think can we best maximize the benefits of cell-free fetal DNA testing capabilities while minimizing the potential harm? Are there regulations or policies that can be implemented that you think would yield a favorable balance of risks and benefits?

Dr. Cho: That’s a good question, but I don’t have a very good answer. Some of the concerns about potentially eugenic uses of cell-free fetal DNA in a prenatal setting are very difficult to address at the policy level, and we haven’t done a very good job of that so far with other kinds of prenatal testing. A lot will depend on such things as informed consent, which has not proven very effective right now for other types of prenatal testing, so it is likely going to be a difficult problem to tackle.

The US Food and Drug Administration might be more willing to regulate this kind of genetic testing than other kinds of genetic testing simply because the nature of the decisions made in the prenatal setting are so much more ethically fraught and important. More specific scrutiny of prenatal genetic testing, putting into play some kind of mechanism for quality control, quality assessment, and accuracy at an analytic level would at least help to minimize some of the risks from having inaccurate results.

But the large social and ethical issues are going to be very difficult to address through policy, and clinicians are going to have a hard time dealing with them. Up to this point, we’ve been very reluctant to interfere with prenatal decision-making. Much of this will probably end up being left to public education efforts, which may be of limited effectiveness.


  1. Kitzman JO, Snyder MW, Ventura M, et al. Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. 2012;4:137ra76.
  2. Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, Quake SR. Non-invasive prenatal measurement of the fetal genome. Nature. 2012;487:320-324. Abstract
  3. Committee on Bioethics. Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;107:1451-1455. Abstract
  4. National Society of Genetic Counselors. Position Statement: Prenatal and Childhood Testing for Adult-onset Disorders. 1995. http://www.nsgc.org/Advocacy/PositionStatements/tabid/107/Default.aspx#PrenatalChildTestingAdultOnsetAccessed July 12, 2012.
  5. American College of Obstetrics and Gynecology. ACOG Committee Opinion: Sex Selection; February 2007 (reaffirmed 2011). http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Ethics/Sex_SelectionAccessed July 12, 2012.

Medscape Genomic Medicine © 2012 WebMD, LLC

Retrieved from: http://www.medscape.com/viewarticle/771190?src=nl_topic



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