Noninvasive Prenatal Screening: Development of Cell-Free DNA Technology and Its Move to Become a Standard of Care
Andrew F. Wagner, MD, FACMG, FACOG
Northwestern University Feinberg School of Medicine
Department of Obstetrics and Gynecology
Division of Clinical Genetics
Screening for fetal chromosomal abnormalities, a part of clinical obstetric practice since the late 1980s, provides families with information to assist them with reassurance, pregnancy and delivery planning, and decisionmaking.1 Initially, these screens were used to assess risks for open neural tube defects and to measure placental and fetal markers during the second trimester to identify an age-related risk for Down syndrome and trisomy 18 (Edwards syndrome).2-4 Advances in ultrasound technology with the nuchal translucency (NT) measurement have expanded such screening into the first trimester.5,6 The laboratory-derived cell-free DNA (cfDNA) screening was made available in the United States in November 2011 with the aim of making these screens more sensitive and lowering their false-positive rate.7 This new form of DNA sequencing technology has rapidly expanded into clinical practice as a reliable, accurate, and popular screen. In response, the American College of Obstetricians and Gynecologists (ACOG) and American College of Medical Genetics and Genomics (ACMG) have published practice bulletins and position statements giving guidance to their membership on how best to integrate this screening into their clinical practice for the benefit of their patients.8,9
Screens and Diagnostic Tests
The concept of screening for chromosomal abnormalities came from the observation that as a woman ages, her chance of conceiving a fetus with chromosomal aneuploidy increases. The initial screen was as simple as asking for the patient’s date of birth. The prenatal diagnostic techniques of amniocentesis and chorionic villus sampling (CVS) were developed as ways to sample prenatally derived cells to obtain a chromosomal karyotype.10,11 As ultrasound technology and its use became more widespread and as education on how to perform these procedures became a standard part of obstetrics training, it became the standard of care to offer such tests to this group of high-risk pregnant women.12,13 However, not every woman was comfortable with the risk of a procedure-related loss. Therefore, screens were developed to assess and personalize risks for chromosomal abnormalities.
The purpose of screens and tests is to give a pregnant woman information, but the results of each are reported in different ways. The prenatal diagnostic tests CVS and amniocentesis are the gold standard and provide definitive results.14 Screens, on the other hand, are not definitive and traditionally provide a numeral risk assessment representing a woman’s chances of carrying a fetus with the chromosomal abnormality in question (TABLE 1, page S12). By stratifying risk, many women rely on screens to determine if they should undergo one of the diagnostic options.8 They may choose to have one of the diagnostic tests initially, and this option is acceptable regardless of risk. In 2007, ACOG’s recommendations through practice bulletins on screening and diagnostic testing explained that all screens and tests should be made available to all women regardless of age.15,16
As these screens developed, their accuracy improved. Traditionally, the serum screens in the first trimester, second trimester (triple, quad), and those integrating first- and second-trimester components (sequential, integrated) all used a screen (false) positive rate of 5%.6 Over time, various technologies allowed for improvements in sensitivity (detection rate) from 69% to 96%. All of these screens utilized markers of placental- or fetal-derived proteins in the maternal serum with or without a specific ultrasound measurement (NT in the first trimester). There are a multitude of reasons why these values can be increased or decreased compared to a normal value, and these can be unrelated to the presence of chromosomal aneuploidy in the fetus.17
To receive CME credit, please read the articles and go to www.omniaeducation.com/NIPT to access the post-test and evaluation.
This supplement is designed to provide ObGyn clinicians with current information on the cell-free DNA screening test options available for fetal chromosomal abnormalities. These screening tests are commonly referred to as Noninvasive Prenatal Screening (NIPS). In August 2020, the American College of Obstetricians and Gynecologists (ACOG) issued a Practice Bulletin entitled “Screening for Fetal Chromosomal Abnormalities” (PB #226). This Practice Bulletin included expanded information regarding the use of NIPS in all patients regardless of maternal age or baseline risk. It also identified NIPS as the most sensitive and specific test for screening for the most common aneuploidies. The authors of this supplement provide additional information on the technology, performance, and clinical utilization of NIPS testing.
Ann Early has nothing to disclose.
Genevieve L. Fairbrother MD, MPH, FACOG has nothing to disclose.
Morry Fiddler, PhD receives a salary from Insight Medical Genetics.
Barry A. Fiedel, PhD has nothing to disclose.
Amanda Hilferty has nothing to disclose.
Robert Schneider, MSW has nothing to disclose.
Lee P. Shulman, MD, FACMG, FACOG receives consulting fees from Biogix, Celula, Cooper Surgical, Natera, and Vermillion/Aspira and is a speaker for Bayer, Lupin Pharmaceuticals, Inc., and Myriad.
Andrew F. Wagner, MD, FACMG, FACOG has nothing to disclose.
Haichuan Zhang, PhD has ownership interest in Celula China Medical Technology Co.
After participating in this educational activity, participants should be better able to:
- Overcome barriers and demonstrate competency in integrating ACOG/Society for Maternal-Fetal Medicine Noninvasive Prenatal Testing Committee Opinions/Practice Bulletins recommendations into clinical decisionmaking surrounding prenatal visits for all pregnant patients.
- Explain the benefits and disadvantages of traditional fetal chromosomal aneuploidy screening tests compared with noninvasive screening tests.
- Define the technology that is the basis of the various noninvasive screening tests, including the role that fetal fraction plays in influencing results.
- Explain the expanding role of NIPS in the general obstetrical population.
ACCREDITATION AND CREDIT DESIGNATION STATEMENTS:
Global Learning Collaborative (GLC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Global Learning Collaborative designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This activity is designed to meet the educational needs of the obstetrician and gynecologist, family physician, internal medicine physician, physician assistant, nurse practitioner, and certified nurse midwife.
This activity is supported by an independent educational grant from Roche Diagnostics.
The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of GLC and Omnia Education. This presentation is not intended to define an exclusive course of patient management; the participant should use his/her clinical judgment, knowledge, experience, and diagnostic skills in applying or adopting for professional use any of the information provided herein. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Links to other sites may be provided as additional sources of information. Once you elect to link to a site outside of Omnia Education you are subject to the terms and conditions of use, including copyright and licensing restriction, of that site.
Reproduction of this material is not permitted without written permission from the copyright owner.
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