Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities

Abstract

Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation.

Keywords: NIPT; cfDNA; cfRNA; genomics; liquid biopsy; noninvasive prenatal testing; prenatal care.

Figure 1

Noninvasive prenatal testing provides a lens into the health of the pregnant individual, fetus, and placenta. (a) Across pregnancy, liquid biopsy tests can measure macromolecules or whole cells present in blood, including cell-free DNA and RNA (cfDNA and cfRNA), white blood cells, proteins, lipids, and metabolites. (b) This approach is useful for the screening and diagnosis of numerous pregnancy-related conditions including genetic disorders, parental cancers and infections, and obstetric syndromes like preeclampsia and preterm birth, thereby helping to guide clinical practice. Figure adapted from images created with BioRender.com.

Figure 2

Representative results for each noninvasive prenatal testing (NIPT) test. NIPT tests that measure cell-free DNA (cfDNA) expect equal representation from all chromosomes. Individual chromosomal imbalances suggest fetal aneuploidy [e.g., trisomy 21 (T21)], whereas genome-wide imbalances involving more than one chromosome suggest maternal malignancy (e.g., cancer). The detection of pathogenic cfDNA or cell-free RNA (cfRNA) sequences suggests infection; the detection of elevated host immune genes or pathogenic RNA suggests active infection. NIPT for prenatal complications typically assess the under- or overrepresentation of specific genes of interest; in combination using predictive models like machine learning, these unusual gene levels can suggest preeclampsia or preterm birth. Figure adapted from images created with BioRender.com.