November 25, 2013. Marta Wegorzewska, PhD candidate, in collaboration with Dr. Seth Bokser, MD. Edited by Tracey McLean, MD.
Every parent dreams about having a healthy baby. Some parents want to know before birth if their child will have a genetic disorder.
Genetic disorders are caused by chromosomal abnormalities. Chromosomes carry DNA that determines characteristics such as height, hair color, and nose shape. Having too much, too little, or mixed up DNA causes problems.
Prenatal genetic testing helps parents who want to know if their baby will be born with a chromosomal abnormality. Today, there are numerous tests available that fall into two categories. Screening tests estimate a potential risk of a genetic disorder. Diagnostic tests confirm the existence and type of genetic disorder.
Traditionally, doctors recommend prenatal genetic screening tests at 10-13 or 16-18 (or both) weeks of gestation.1 Maternal blood is screened for markers associated with chromosomal abnormalities.2 An ultrasound reveals abnormal physical characteristics on the growing fetus.3
When these traditional screening tools indicate a high likelihood of a genetic problem, women are referred for diagnostic tests that give definitive information about chromosomal mishaps on fetal DNA.
Where does the fetal DNA come from? Fetal DNA is found in the fluid the fetus swims in (amniotic fluid) or in the placenta (chorionic villus). Getting a sample of fetal DNA involves invasive procedures (amnioscentesis, chorionic villus sampling) that carry a small risk of miscarriage but are very good at diagnosing chromosomal problems.4,5
Recently, finding fetal DNA has gotten easier. Scientists discovered fetal DNA in the mother’s blood!6 Some chromosomal abnormalities can now be detected from a maternal blood sample.7-10
Four companies (Verinata, Sequenom, Ariosa, and Natera) have packaged this idea into new non-invasive prenatal tests (NIPT: Verifi, MaterniT21, Harmony, Panorama, respectively) available to most women. The tests are done early in pregnancy and the results come back in about a week.
The best part is only a small sample of blood is needed. What is the catch?
The Fine Print
Because this exciting technology is brand-new, it is not surprising NIPT have some limitations.
1. They are available to most women, BUT we do not always know how to interpret the result. The original validation studies used blood from women whose fetuses were known to have chromosomal abnormalities.7-11 We don’t know what the results mean for the general population or for women carrying multiple pregnancies (twins, triplets etc).
2. They are sensitive and specific,7-10 BUT we do not know if they are clinically useful. The companies have shown that the the tests perform well technically. They are sensitive, meaning if a patient has a disease, the test is likely to find it. We also know the tests are specific, meaning if a patient does not have the disease, the tests will most likely come back with a negative result. Both sensitivity and specify affect how well the tests perform, but it is does not help physicians answer an important question. “If a test gives a positive result, what is the chance the fetus will have a genetic condition?” This is called predictive value and describes how clinically useful the tests are. How well a result translates to a clinical outcome is crucial information because for some women the result may mean making a very difficult decision about the pregnancy.
3. It is easy and non-invasive BUT limited. The new test detects fewer genetic abnormalities than the traditional screening tests. A negative result on the new test does not rule out rare chromosomal abnormalities.
What does this mean for you?
The medical community has recognized the value and limitation of this test. The following recommendations have been made:12
1. The test is not recommend for low-risk women. It is also not recommended for women carrying multiple pregnancies. The results in these populations are difficult to interpret and are based on what is known in the high-risk population. Insurance will not cover the cost of the test for these women.
2. High-risk women can choose between the new, non-invasive test and the traditional invasive test. Insurance will cover the new test in this scenario only. Because no information is available at this time about how clinically useful the test is, it is difficult to predict the odds a positive result will translate to a genetic condition. Even if the new test is performed, the invasive tests are recommended to confirm the result.
3. High-risk women with a family history of a genetic condition not detected on the new test are advised to get the traditional screening test and the invasive tests.
The new test entered the market very rapidly. Its fast, easy and non-invasive properties are emphasized to entice buyers. The new non-invasive test may represent a big leap forward, but the science needs time to catch up! If you choose to proceed with the test, know:
1. It’s only recommended as a screening and not a diagnostic tool. If you want a diagnosis, you will need to decide if you want the more invasive tests performed.
2. Its screening abilities are more limited than the traditional screening tests.
How does this information change what you thought about the new non-invasive prenatal test?
This post is checked by the following science articles:
1. Borrell A, Casals E, Fortuny A, Farre MT, Gonce A, Sanchez A, Soler A, Cararach V, Vanrell JA. First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study. Prenat Diagn. 2004 Jul;24(7):541-5.
2. Brambati B, Macintosh MC, Teisner B, Maguiness S, Shrimanker K, Lanzani A, Bonacchi I, Tului L, Chard T, Grudzinskas JG. Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype. Br J Obstet Gynaecol. 1993 Apr;100(4):324-6.
8. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011;342:c7401.
9. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol 2011;204:205.e1–11.
11. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20.