Introduction

When Denis Lo and his colleagues in Oxford identified the presence of free fetal DNA in the blood of pregnant women, the implications for prenatal diagnostics without the requirement for invasive procedures were obvious. The main complication is that a very low concentration of fetal DNA is present in the maternal plasma, representing between 3% and 6% of the total free DNA. Although enrichment of fetal DNA can be achieved by exploiting the differences in fragment size between fetal and maternal DNA, complete separation has not proved possible. The only diagnostic tests using free fetal DNA in maternal plasma that are used routinely are those where the target gene or allele is not present in the mother. These are fetal sexing by detection of a Y-borne gene and fetal blood grouping in women whose red cells lack the corresponding antigen.

Alloimmunisation against the D (RH1) red cell surface antigen of the Rh blood group system is the most common cause of haemolytic disease of the fetus and newborn (HDFN), which, before the introduction of post-delivery anti-D prophylaxis in the 1960s, accounted for the death of one baby in 2200. In the following 40 years, the effect of the anti-D prophylaxis programme and improved neonatal care reduced the prevalence to one death in 21000. In England and Wales, about 500 fetuses develop HDFN each year, of which 25–30 babies die, and at least 20 pregnancies per year are lost to miscarriage before 24 weeks of gestation.