Noninvasive Prenatal Genetic Diagnosis Raises Clinical, Ethical Challenges

Jacquelyn K. Beals, PhD

January 19, 2011

January 19, 2011 — Prenatal genetic testing has taken a new leap forward thanks to studies by separate groups in the United States and Hong Kong showing that thousands of loci in the fetal genome can be analyzed from a 10-mL sample of maternal blood. The implications of noninvasive prenatal genetic diagnosis (NIPD) are weighed in a comment published in the January 20 issue of Nature.

Current methods of fetal genetic analysis include amniocentesis, based on the cells in a small sample of amniotic fluid, and chorionic villus sampling, using fetal cells from the placenta. These procedures increase the miscarriage risk, and samples can be used for only 1 or 2 genetic tests — most frequently, detection of abnormal chromosome number.

The new tests are based on fragments of fetal DNA from cells that have died and been digested by enzymes. Free-floating DNA fragments end up in the mother's bloodstream.

"Even early in pregnancy, 5–10% of that 'cell-free' DNA in pregnant women comes from the fetus," writes author Henry T. Greely, JD, professor of law, Center for Law and the Biosciences, Stanford Law School, California.

NIPD can not only detect abnormal chromosome number but also analyze thousands of sites in the fetal genome. With no maternal risk (just a 10-mL blood draw), and decreasing costs of genotype and sequencing technology, the new test faces few if any barriers to wide acceptance by clinicians and patients.

Clinical, Social, Ethical Questions

It is the ease of the test and its almost inevitable acceptance that raise clinical, social, and ethical questions, suggests Dr. Greely. Although fewer than 2% of pregnant women in the United States currently have amniocentesis or chorionic villus sampling, the new test yields more information, adds virtually no risk, and eliminates the distinctly sobering aspect of procedures that employ a large needle or a transvaginal probe.

Another source of ethical concern is the fact that NIPD testing can be performed earlier in pregnancy. "That may lead people to feel more comfortable about ending a pregnancy for whatever reason they may have," commented Arthur L. Caplan, PhD, professor of bioethics, Department of Medical Ethics, University of Pennsylvania School of Medicine, Philadelphia, in a telephone interview with Medscape Medical News.

"It's one thing to find out that your baby has a problem when the baby is 20 weeks, almost to viability. It's different when you can use circulating cells to do a test and find out about your baby at 8 or 9 weeks," said Dr. Caplan. "Some people oppose abortion or ending pregnancy under any terms, but for many, earlier is morally less troubling."

Advocates for the disabled may also be troubled by a test that makes prenatal detection so simple, with accompanying concerns about devaluation of the disabled and the potential decrease of research into disability prevention and treatment.

Fears of eugenics, already raised by current technologies and in vitro fertilization, also may be magnified many times. When a test becomes so free of stress, the potential for "trivial" uses is likely to increase: A test designed to detect moderately severe genetic abnormalities could move to sex determination (already common for in vitro fertilization), appearance, and physical or intellectual ability.

Issues of Oversight, Regulation

Dr. Greely's article also notes issues of oversight and regulation of the new tests, such as how to ensure their proper performance and accurate interpretation. There are also financial concerns about who should pay for the test and for possible subsequent termination of pregnancy. Insurance companies and healthcare systems may regard the tests as "preventive medicine," preventing the birth of children who would require extensive medical and social support, according to Dr. Greeley. In contrast, once these tests are commonly available, failure to use them could open the door to "wrongful birth" suits against physicians or parents.

Based on the widespread use of noninvasive screening for Down's syndrome in California, Dr. Greely estimates that NIPD might well increase the number of pregnant women electing to be screened from 100,000 to 3 million per year, greatly expanding the need for genetic counselors.

"The possibility that, in countries with good healthcare systems, a majority of pregnant women might get prenatal genetic testing means the possibility that a majority of children who might have been born with serious genetic diseases will instead not be born," said Dr. Greely via email to Medscape Medical News. "That will affect those already born with those diseases, as well as those who continue to be born with them."

The situation is even more complex because NIPD is able to identify hundreds of genetic glitches, rather than the few most often assessed by current tests. "Now we test mainly for Down's syndrome and a few other rarer aneuploidies, or we test for the one genetic disease that has run in the particular family," Dr. Greely observed.

"[With NIPD] we'll be testing for 100 diseases or traits. How do you do the informed consent for that? How do you provide information about those diseases? Who will do the counseling and how? And how can we help pregnant women take in and process all this information?" asked Dr. Greely. "I think that will be, in the clinical context, quite challenging."

Focused Education to Come

One might expect continuing medical education or medical school to provide the requisite training, but "It's more likely [that] for educating people about this testing, there's going to be focused education on the people who deal with childbirth, genetic counselors, nurses who work with [obstetricians]," Dr. Caplan observed. "In medical school, there's a lot competing for attention. No matter what you did, this isn't going to take up a big section of the curriculum."

Dr. Greely urges professional organizations in genetics and medicine to become involved in drafting guidelines and training related to NIPD, but notes that at present, the associated ethical and medical issues are receiving more attention in the European Union than in the United States.

"[T]his is an area where people don't really want to get involved because you're talking about fetuses, abortion, eugenic selection of traits," Dr. Caplan observed. "It's just very hard to get politicians here to pay any attention to that. It falls to the bioethics community to pay attention.

"Some of the medical groups should be trying to set some standards, so I think Dr. Greely's comments in that regard are solid. But in terms of state legislators or federal legislation coming into this area any time soon," said Dr. Caplan, "I wouldn't look for it."

Dr. Greely and Dr. Caplan have disclosed no relevant financial relationships.

Nature. 2011;469:289-291.

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