Trisomy 21 (Down Syndrome) is the commonest fetal aneuploidy (abnormal chromosome) and a prenatal screening for Trisomy 21 (Down Syndrome) is routinely offered to all pregnant mothers. The current assessment involves a noninvasive risk assessment for the most common aneuploidies, before invasive prenatal procedures are offered.
The current assessment methods
The prenatal risk assessment involves an ultrasound measurement of nuchal translucency (NT), together with different maternal serum biochemical screening tests, either in the first or second trimester. At the moment, the most used noninvasive screening test for individual trisomy 21 (Down syndrome) risk calculation worldwide is the combined test.
The combined test includes a serum screening test containing two blood markers, namely pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotrophin, combined with nuchal translucency measurement. Alternatively, triple test is performed in the second trimester.
When the screening assessment indicates high-risk for a trisomy 21 (Down syndrome), 18 (Edwards syndrome) or 13 (Patau syndrome), a confirmatory test is indicated. An invasive prenatal diagnosis via amniocentesis or chorionic villus sampling to obtain the fetal cells for karyotyping or rapid aneuploidy detection is performed. These invasive procedures are associated with a risk of miscarriage ranging from 0.6%, within 14 days of the procedure, to 2% for total pregnancy loss.
Noninvasive cell-free DNA test- a better alternative
To avert this risk of miscarriage, there is an increasing demand for a reliable and safe noninvasive prenatal test that is applicable as early in pregnancy as possible. Since the discovery of the presence of cell-free fetal in maternal blood, the possibility of using this as the target for noninvasive prenatal testing (NIPT) of fetal genetic conditions is being explored widely. The cell-free fetal DNA represents a subfraction of 6–10% of the total cfDNA in first and second trimester pregnancies and rises up to 10–20% in third trimester pregnancies. Various molecular analysis can be performed to obtain a more accurate risk assessment, avoiding unnecessary invasive procedure.
The diagnostic parameters of NIPT of trisomy 21 are better than those of the current first trimester risk assessment. Large cohort studies showed variable levels of sensitivity (58.82–100.00%) with, in general, higher levels of specificity (83.33–100.00%). The later NIPT studies using more advanced molecular technique (MPS) have an improved sensitivity, ranging from 98.58% to 100.00%, as well a specificity, from 97.95% to 100.00%. These NIPT techniques exhibit an excellent NPV in natural conditions with disease odds up to 1:200.
The NIPT is likely to be the ideal tool for prenatal risk assessment, as a replacement over the current serum screening test. Due to the low false-positive and false-negative results, fewer trisomy cases would be missed at the first screening step and fewer invasive procedures would be needed, to verify a positive NIPT result.
However, before NIPT of trisomy 21 can replace the current serum screening test more evidence is needed from large prospective diagnostic accuracy studies, including suitability in low-risk pregnant women early in pregnancy. Moreover, the issue of cost effectiveness when used in low risk population should also be addressed. Finally, further ethical exploration and evaluation of the current opinion of pregnant women and the formulation of proper informed consent information are needed.
Molecular NIPT of trisomy 21 is a promising test and has an important role in prenatal diagnosis and possibly in prenatal screening in the coming years