Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.
In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."
The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).
October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.
"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.
Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.
The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).
None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.
The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.
Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.
Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.
Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.
Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.
A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).
In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).