Progress toward Noninvasive Prenatal Diagnosis

Abstract

For decades, noninvasive analysis of the fetal genotype has been the holy grail of the field of prenatal diagnosis. Noninvasive prenatal diagnosis (NIPD)2 would use a sample source other than amniocentesis or chorionic villus sampling. The focus has been primarily on the use of maternal blood samples, with less attention given to the possibility of recovering fetal cells from maternal cervical samples (as would be collected for cervical cancer screening). The initial efforts focused on the presence of fetal cells in the maternal circulation, and evidence indicated as early as 1979 that fetal cells could be recovered via fluorescence-activated cell sorting. The elegant strategy of using antibodies to paternal HLA antigens to identify fetal cells was demonstrated. Attempts to recover fetal cells focused for a time on fetal nucleated red blood cells via analysis with fluorescence in situ hybridization and the PCR, but the disappointing results led to skepticism that NIPD would ever become a reality. By 1996 there were reports of tumor DNA detected in the plasma of cancer patients, and Lo et al. first reported in 1997 the presence of fetal DNA in maternal plasma. The use of fetal DNA in the plasma has important advantages over the use of fetal cells in that fetal DNA can be obtained consistently in virtually 100% of pregnancies, whereas fetal cells are recovered much less consistently. In recent years, the use of fetal DNA in maternal plasma to detect fetal sex has become a well-established clinical test [see references in Lo et al. (1) for background on this test and other details]. In fact, determining whether any genotype present in the father but not the mother has been transmitted to the fetus is relatively straightforward. This approach has been used to determine whether a fetus is Rh negative or positive …