The management of pregnant women from a genetic angle centres on combined first trimester screening (“first-trimester screening”).

This aims to detect the common trisomies, and above all trisomy 21, responsible for Down syndrome, as well as trisomies 18 and 13. The three components making it possible to determine the risk of trisomy include ultrasound measurement of nuchal translucency (NT), a blood test measuring two biomarkers (PAPP-A and B-hCG), and the mother's age.

If the risk is intermediate (>1:1,000 but <1:100 or <1:50) then non-invasive genetic testing (NIPT) is indicated. Free fetal DNA extracted from maternal blood is of placental origin, emanating from the cytotrophoblast. The fetal-maternal DNA mixture is analyzed using different technologies (usually high-throughput sequencing or NGS). Three types of tests are available:

(i) one is limited to detecting the three main trisomies – trisomies 21, 18 and 13 – while the two others
(ii) also detect gonosomal abnormalities, and
(iii) also rare autosomal trisomies and structural chromosome abnormalities (CNVs).

NIPT for the three common trisomies: this version of NIPT is universally accepted and its performance in terms of sensitivity and specificity is substantially superior to that of the first-trimester test (N Engl J Med 2015; 372:1589-1597).

There is disagreement regarding NIPT that includes gonosomal abnormalities. Firstly, it allows the sex of the foetus to be determined, opening the door to potential abuse, and secondly, the clinical impact of gonosomal abnormalities is generally underestimated by non-specialists. In other words, some practitioners maintain that the clinical severity of gonosomal abnormalities is less than that associated with Down syndrome.

The most complete version of NIPT detects all categories of abnormality mentioned above (Genet. Med. 2017; 19:169-175). Prescription of this test must be preceded by expert counselling, provided before screening takes place, to highlight its superior [diagnostic] yield but also its unnecessary results.

Expert advice needs to be given prior to first-trimester screening and NIPT. A number of important points need to be addressed, and particularly the right not to know, plus some other technical aspects.

In the case of the first-trimester screen, this means that the suboptimal sensitivity of the test and its rate of false positives, which is quite high, need to be addressed.

With respect to NIPT, it is important to discuss the placental origin of foetal DNA, implying that a chromosomal abnormality may be limited to the placenta and therefore, an additional examination - amniocentesis - may be necessary to confirm or not an anomaly.

Women should also be warned about abnormalities that require further follow-up and screening, even if the 1st trimester test and NIPT are normal, such as increased NT, hydramnios, and sonographic or growth abnormalities.

Genesupport - NIPT for the most common trisomie