The Pros and Cons of Noninvasive Prenatal Screening

Laura A. Stokowski, RN, MS; Susan Klugman, MD


November 07, 2013

Editor's Note:
Noninvasive prenatal screening, using cell-free fetal DNA circulating in maternal blood, offers an early method of detecting certain fetal chromosomal abnormalities. As a new technology, many uncertainties exist about the place of noninvasive prenatal screening in the management of pregnancy, and it will take time for guidelines and recommendations on the use of this type of screening to be formulated and disseminated. In the meantime, these tests have made so many headlines that clinicians must be ready with answers when women come in to the office asking for the test.

Medscape spoke with Susan Klugman, MD, Director of Reproductive Genetics at Montefiore Medical Center in New York City, about what clinicians need to know about nonvinasive prenatal screening.

Medscape: How does noninvasive genetic testing fit in with existing prenatal tests for chromosomal aneuploidies?

Dr. Klugman: The field of prenatal genetic testing is evolving exponentially. There are genetic tests and genetic screens, and the difference between them is very important for both the clinician and the patient to understand.

First we had the triple screen, and then the quadruple screen, and then the first-trimester screen. We also use ultrasonography to look for structural abnormalities. Then in 1997, it was discovered that cell-free fetal DNA could be isolated from maternal blood, so a screening test was developed to identify the same 3 trisomies -- trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome) -- that we were looking for with first-trimester screening.

Medscape: Who can be offered noninvasive prenatal screening?

Dr. Klugman: The noninvasive screening tests were validated in a population of high-risk women. In accordance with the American College of Obstetrics and Gynecology (ACOG) guidelines,[1] it is only recommended for high-risk women at the present time. High-risk women are those with:

Advanced maternal age (> 35 years);

A positive triple or quadruple or first-trimester screen;

A structural finding on ultrasonography suggesting aneuploidy;

A previous trisomy birth;

A known balanced translocation in a parent or the parent of the partner.

Women might know that last indication if they had a previous infant with a translocation, or if a translocation was seen on a specimen from a miscarriage. Women who are at increased risk for a trisomy pregnancy because of one of these reasons can be offered noninvasive screening regardless of maternal age.

In New York State, the noninvasive prenatal screening test can only be used according to those guidelines, so at the present time, it cannot be offered to low-risk women. We don't know the sensitivity of the test in low-risk populations because they weren't included in the original validation testing. The accuracy of the test in multiple gestation pregnancies is not known either, so the test can't be offered to these women.

Medscape: Commercially developed noninvasive prenatal screening tests have entered the market very rapidly in the last few years. How different are the various tests on the market, and how does the clinician decide which test to order?

Dr. Klugman: Right now, there are 4 different noninvasive prenatal screening tests available from 4 different companies. Three of them use similar platforms, and 1 is slightly different. These tests are offered only through commercial laboratories, so they can't be done at the hospital or university-based clinical laboratory. They have to be sent out, and results take about a week.

The tests currently on the market screen only for the 3 trisomies I noted earlier. Some also screen for fetal sex and sex-chromosome aneuploidies.

The biggest difference between available noninvasive screens right now, from the patient and clinician perspective, is cost. Some are partially covered by insurance, but this is highly variable, as is the amount of copay and out-of-pocket cost for the patient. The tests can cost in the range of $800 to $3000, but many laboratories cover most of this cost except for a few hundred dollars. This varies by laboratory and insurance.

Medscape: You were involved in a study[2] of chromosomal microarray testing from samples obtained during amniocentesis or chorionic villus sampling (CVS). How does this differ from noninvasive prenatal screening, in terms of the information available to women about the health of the fetus?

Dr. Klugman: Chromosomal microarray is a test that is currently done in addition to karyotyping after an invasive test, such as a CVS or amniocentesis, and invasive testing can be offered to any pregnant woman -- it is not limited to only those women determined to be high risk. Chromosomal microarray gives a lot more information than the noninvasive prenatal screening tests.

With chromosomal microarray, we can find out about, and rule out, hundreds of disorders. Microarray permits the detection of small genetic deletions and duplications (called "copy-number variants") that are not routinely seen on karyotyping. As with karyotyping, however, findings of unknown significance on chromosomal microarray can sometimes present challenges for clinicians and create anxiety in parents.

Medscape: How early can noninvasive screening tests be done? Do any factors influence the accuracy of the test, such as weeks of gestation?

Dr. Klugman: The test can be done as early as 10 weeks and is typically offered up to 20 weeks after a woman has missed her period, so a little earlier than CVS. If the maternal blood is sampled too early, the fraction of fetal DNA can be too low, and the test can return an inconclusive result.

Another factor that can affect the results is obesity. In the plasma of obese women, the fetal fraction of DNA is lower and can produce an inconclusive result. With the increasing prevalence of obesity, we are likely to encounter this problem more often.

Medscape: How should clinicians respond when a patient comes in asking for noninvasive prenatal testing?

Dr. Klugman: Because noninvasive prenatal screening is not offered to every patient, it can't just be included in "routine" prenatal tests. It requires an individual discussion with every patient who is interested in screening.

The difficulty for the clinician is the need to accomplish this at the first prenatal visit, along with the necessary discussion of general prenatal care, blood tests and sonograms, nutrition, diet, vitamins, weight gain, smoking, alcohol, drugs, and all of the other things that have to be covered at that visit. The purpose and implications of noninvasive prenatal screening cannot be adequately addressed in a couple of minutes. The decision to have the test must be an informed choice.

If a woman is thinking of pursuing noninvasive prenatal screening, we recommend that a separate visit be scheduled, either with the obstetric clinician or with a genetics provider who is well versed in the screen, to go over noninvasive prenatal screening in more detail. However, we may not have enough genetic counselors to offer pretesting counseling sessions to all women.

Medscape: How should clinicians prepare women for noninvasive prenatal screening?

Dr. Klugman: Most patients don't really understand what they are getting with the test, so they need to be educated about what the test screens for, and the limitations of the test. It's critical for patients to be informed. Of greatest importance, they need to realize that although it is highly sensitive and specific, noninvasive prenatal screening is not a diagnostic test. It is a screening test. That means that if the test is positive for a fetal trisomy, the woman will have to undergo invasive testing if she wants confirmation. Obviously, a woman has a choice -- she does not have to have invasive testing.

Similarly, women who don't want noninvasive prenatal screening can still have the choice of first-trimester screening or quadruple screening. They need to realize that noninvasive screening does not provide the same information as tests done on samples obtained from amniocentesis or CVS.

Women need to know that the noninvasive screen will not provide any genetic information other than the 3 aneuploidies and sex chromosomes. It will not tell them about the presence or absence of other genetic disorders or diseases that might run in their families, or reassure them that their infant will not have other birth defects. It does not screen for neural tube defects.

Medscape: How should clinicians explain the results of noninvasive prenatal screening to women?

Dr. Klugman: Just like many other laboratory tests, false-positive results are possible, so these women should be offered invasive testing to confirm or rule out the aneuploidy suggested by the noninvasive screen. In a small number of cases, no result will be possible, or additional blood might be needed to get a result. It is important to keep the big picture in mind when evaluating results. If a structural anomaly suggesting a trisomy has been found on ultrasonography, and the screening test comes back positive for a trisomy, that is concordant.

On the other hand, women need to understand that a negative screening test doesn't guarantee that everything is normal and nothing else will go wrong.

It is recommended that couples be scheduled for a session with the clinician or a genetics counselor to thoroughly review the significance of a positive noninvasive prenatal screening test and receive counseling about invasive testing, associated risks, and what this can offer in terms of confirmation or additional information.

This is often a very stressful time for a pregnant woman. She is trying to squeeze in a prenatal visit to have these tests, and important decisions must be made often before she is "showing" or has even discussed the pregnancy with friends or family.

Medscape: Do you expect noninvasive prenatal screening to replace invasive testing, such as amniocentesis or CVS?

Dr. Klugman: We are still at an early stage with the clinical use of this technology. It is possible that it could eventually replace invasive testing, but we need a lot more information than is currently provided by the versions on the market right now. Researchers claim to be able to perform a complete microarray on a single cell. The only thing holding them back is cost, so we will have to wait and see the further developments with this technology.

For now, noninvasive prenatal screening definitely has a place in prenatal genetic assessment. Women can get reassurance that their unborn babies don't have 1 of the 3 trisomies (13, 18, and 21) or a sex-chromosome disorder, if the screen includes that. Noninvasive screening is viewed as an option, along with triple or quadruple screens and first-trimester ultrasonography.

Medscape: Do you have any other advice for clinicians who are considering offering noninvasive prenatal screening to their patients?

Dr. Klugman: Clinicians need to be comfortable with and able to educate patients about the noninvasive prenatal screen, understanding that it is a screening test and not a diagnostic test. They need to be able to discuss the limitations of the test with patients, including the populations in whom the test is validated. They need to explain the significance of test results: positive, negative, or "uninformative." They need to be well versed in insurance coverage (or lack thereof), copays, and out-of-pocket expenses for the test. If clinicians aren't comfortable discussing all of these issues, they should refer the patient to someone who can, such as a genetic counselor, geneticist, or maternal/fetal medicine specialist.

Clinicians must remember that every patient is different, and they need to maintain an individualized approach with each patient. How to convey all of the information needed for the patient to make an educated choice is a real dilemma for obstetric providers right now. Research hasn't sorted out the best way to accomplish this, whether with reading material, group vs individual sessions, or individual vs partner counseling. It's a lot to take on, and clinicians need to decide whether they are ready. National guidelines are still in development or have only recently been developed. Hospitals and practices are trying to formulate their own guidelines, policies, and procedures for the use of noninvasive prenatal screening, but these may not be in place yet.


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