Cell-free fetal DNA in the maternal serum and plasma: current and evolving applications

Purpose of review Free fetal nucleic acids, found in the plasma of every pregnant woman, have made a substantial impact on prenatal diagnosis. The past decade has seen the introduction of routine noninvasive prenatal diagnosis (NIPD) using DNA extracted from maternal plasma for a number of clinical complications of pregnancy, notably feto-maternal blood group incompatibility, fetal sexing and exclusion/detection of single-gene disorders. It appears that mass-scale analysis of all RhD-negative pregnant women will be adopted to conserve stocks of prophylactic anti-D and avoid the administration of a blood product unnecessarily. For the majority of prenatal diagnostic procedures, the assessment of trisomy, particularly trisomy 21, is the highest priority. Because RHD genotyping, fetal sexing and analysis of single-gene disorders all depend on the detection of paternally inherited alleles, they were relatively simple to adapt on the basis of PCR analysis of DNA obtained from maternal plasma. However, for assessment of chromosome copy number, this is not so straightforward. Recent findings The assessment of polymorphisms among placentally expressed mRNAs found in maternal plasma has enabled the detection of trisomy 21 fetuses using a combination of reverse transcriptase PCR and mass spectrometry to define allelic ratios of maternally and paternally inherited single nucleotide polymorphisms. Interesting recent developments also include the finding that direct sequence analysis of maternal plasma extracted DNA using 'next-generation' DNA sequencers can differentiate between normal and trisomy fetuses. Summary NIPD using nucleic acids obtained from maternal plasma and serum is now a clinical reality, particularly in the management of hemolytic disease of the fetus and newborn. Recent advances signal that NIPD for common aneuploidies will soon be possible.