Since 2011, prenatal screening for chromosome abnormalities has undergone a paradigm shift as test positive predictive values skyrocketed from a dismal 4% to over 45%. The evolution of prenatal screening is due to short fragments of cell-free fetal DNA that circulate in maternal blood. These cell-free DNA fragments provide a glimpse into fetal health without any risk to the fetus. Attendees of yesterday’s plenary by Rossa Chiu, MBBS, PhD, heard about the game-changing advances in prenatal testing, much of which has been developed by Chiu and colleagues.

The promise of cell-free DNA for prenatal screening may not have been realized without Chiu’s meticulous experimentation as a graduate student. After completing her medical training, Chiu pursued clinical chemistry training at the Chinese University of Hong Kong in 1999 with the stipulation that she would study with Yuk-Ming Dennis Lo, MD, the 2015 AACC Wallace H Coulter Lectureship Award winner. The timing was crucial because Lo had just published the first evidence that fetal cell-free DNA is present in maternal circulation. This set the stage for Chiu’s subsequent research investigations.

Pre-analytical variability is a familiar challenge for all disciplines of laboratory medicine. When Chiu started her graduate work, cell-free DNA as an analyte had been questioned in the literature due to its low abundance and apparent intra-individual variability. Chiu described her trial and error experiments that ultimately standardized blood sample processing for isolation of cell-free DNA. Her method is now used in all cell-free DNA clinical applications including cell-free DNA solid organ transplant monitoring and circulating tumor DNA in oncology.

In addition to developing new methods for prenatal screening, Chiu described her clinical experience expanding the knowledge base of prenatal chromosome abnormalities. For example, obstetric dogma holds that fetuses carrying uncommon chromosome abnormalities are spontaneously lost in the first trimester. Chiu’s group and others in this area have discovered that approximately 0.3% of prenatal cell-free DNA screens are mosaic for a less common chromosome trisomy. As Chiu said, their findings “…challenge the original thought that these rare trisomies would abort in the first trimester. We now know that is not true.” This is clinically important because these rare trisomies are associated with pregnancy complications and fetal demise.

Chiu imagines a new era of prenatal care whereby fetuses can be assessed for an expanded range of conditions beyond chromosome abnormalities. Her group has successfully detected both recessive and dominant inherited conditions as well as conditions that newly arise in the fetus. Through a series of universal probes that identify mutations by haplotype, Chiu has cleverly adapted cell-free DNA to detect fetuses with single gene disorders. In a nod to bedside medicine, she also described her work exploring the use of handheld sequencing devices for detecting fetal cell-free DNA from maternal plasma.

There are many public health and ethical implications of these advances in prenatal genetic testing and Chiu emphasized that these must be considered. With Chiu leading the pack, the future of prenatal testing will undoubtedly include more information that will enable better decision-making about pregnancy management. Chiu concluded, “There is a lot of innovation that has been done to continue to drive applications in this area so that we will be able to maintain the wellness of pregnancy.”