Cell‐free fetal DNA: the new tool in fetal medicine

Since the discovery of cell-free fetal DNA (cffDNA) in maternal plasma in 19971 there has been rapid progress in harnessing this as a source of fetal genetic material for prenatal diagnosis. The majority of cell-free DNA (cfDNA) is maternal in origin2, with the fetal proportion emanating from the placenta3, detectable in the maternal circulation from around 5 weeks’ gestation2 and constituting around only 10% of cfDNA in early pregnancy4. However, as cffDNA is cleared rapidly from the maternal circulation after delivery, it offers great potential as a source of fetal genetic material for prenatal diagnosis5. Initially, in view of the high background of maternal cfDNA, technological restrictions only enabled the detection or exclusion of alleles that were not present in the mother but were present in the fetus because they were paternally inherited or arose de novo at conception. Thus, early indications were for fetal sex determination using Y-chromosome alleles6, fetal Rhesus D (RhD) genotyping in RhD-negative mothers7,8 or for the diagnosis of certain genetic conditions, such as achondroplasia9, in which the majority of cases arise as a result of a new mutation. Technological advances associated with the development of next-generation sequencing (NGS) have enabled accurate counting of DNA sequences that are associated with specific chromosomes10,11 present in maternal blood, which has allowed very rapid development of non-invasive prenatal testing (NIPT) for aneuploidy12. Furthermore, quantification of cffDNA may also be useful in the early identification of pregnancies at risk of other adverse outcomes, such as pre-eclampsia and fetal growth restriction (FGR)13,14. These developments are delivering the biggest change seen in antenatal care over the last few decades, as the need for invasive diagnostic testing reduces dramatically. It is also likely that they will impact on the need for some therapeutic interventions, such as in-utero fetal transfusion, as well as offering a new diagnostic tool in fetal medicine for diagnosis of a dysmorphic fetus and earlier diagnoses in pregnancies at prior risk of a genetic disorder. Here, we review the potential of cffDNA, highlighting its use in fetal medicine, and discuss how it is impacting on the practice of fetal medicine.