The search for prenatal detection of chromosomal anomalies has been ongoing since the 1960s. At the very beginning, maternal age was the screening parameter of choice, and Down syndrome the anomaly that was almost exclusively screened for. Since then things have, at least technically, changed enormously, even though Down syndrome is still the main focus of screening and in the minds of many patients the only diagnosis that they may confront. Structural chromosomal anomalies and monogenic diseases are still not focused on by current screening algorithms, nor by the education system or by society in general. With the clinical implementation of non-invasive prenatal testing (NIPT) in 2012, there has been a paradigm shift in prenatal screening. First trimester combined screening (FTCS) based on maternal age, fetal nuchal translucency thickness (NT) and the serum markers β-HCG and PAPP-A has a detection rate (DR) of 90–95%, a false positive rate of 2.5–5% and a PPV of 3.4 for the detection of trisomy 21. Included is the advantage that, if the results are abnormal, it could raise suspicion not only for the common trisomies, but also for early detectable fetal structural defects and other clinically relevant findings such as rare autosomal trisomies (RATs), triploidy, single gene disorders and copy number variants not detectable in a targeted NIPT approach. A disadvantage is the comparatively high false positive rate leading to invasive procedures.

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.