Prenatal diagnosis is the set of tests aimed at detecting a possible disease in the foetus during pregnancy. A high percentage of these congenital diseases are genetic. Down syndrome, which is due to the presence of three copies of chromosome 21 instead of two, known as trisomy, is the most common genetic syndrome, with an estimated prevalence of 1 in 680 births. This syndrome, like other chromosome number alterations such as Edwards’ syndrome or Patau’s syndrome, is strongly associated with maternal age over 35 years. A few years ago, we only had the combined first trimester screening, which combines the measurement of two hormones, beta-HCG and PAPPa, the measurement of nuchal translucency and maternal age, to select a population of pregnant women for invasive testing. But this screening has a false negative rate of 0.5-9% and a false positive rate of 5%.
Therefore, all patients over 35 years of age and who had an abnormal result from the combined screening were recommended for invasive testing, with a large number of invasive tests being performed in cases where they were not necessary. Invasive tests extract fetal material from chorionic villi, at 12-13 weeks of gestation, or from amniotic fluid, from week 15 onwards. These techniques allow us to confirm the diagnostic suspicion of a syndrome, and although they are safe techniques, they have an estimated fetal loss rate of 0.5-1%.
In 1997, Dennis Lo described the existence of free fetal DNA of placental origin in maternal blood. This finding opened up new possibilities in the field of prenatal diagnosis, since it was thought that in the future it would be possible to detect possible genetic anomalies in the fetus with just a single maternal blood sample. Thanks to the advent of mass sequencing, this goal could be achieved. In 2011, Dennis Lo’s group published a paper in which in a total sample of 753 pregnant women, they were able to detect the presence of chromosome 21 trisomy in maternal blood with a sensitivity of 100% and a specificity of 97.9%. From that year 2011, a test allowing the detection of trisomy 21 in maternal blood began to be marketed.
This was a revolution in the field of prenatal diagnosis, as it allowed for more accurate, earlier and safer detection.
In the last decade, both the scientific literature and medical societies have endorsed the study of foetal DNA in maternal blood as a non-invasive method for detecting the most prevalent chromosomal alterations and recommend the test to all pregnant women, especially those over 35 years of age. This non-invasive test is also recommended for patients with a history of gestational losses and when trisomy is suspected during gestation, either due to an altered biochemical screening or the presence of subjective ultrasound markers. This test can be performed from the 10th week of gestation, at which time it is considered that there is sufficient foetal DNA in maternal blood, as we need a foetal fraction of at least 3.5%. This test can also be performed in twin pregnancies as well as in pregnancies achieved through gestational donation.
Today, we are not only able to detect trisomies 13, 18 and 21 by non-invasive testing. This technology allows us to detect trisomies or monosomies in all foetal chromosomes and microdeletions and microduplications with a resolution of up to 5 Mb.
In this way, the range of anomalies that cause malformation and intellectual disability and that can be detected noninvasively during pregnancy is considerably expanded. The reduction in the cost of sequencing techniques in recent years has allowed more and more patients to have access to these genetic studies.
