No‐call non‐invasive prenatal testing gives important information

Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA fragments in maternal serum samples (cffDNA) is a well-established method for Down syndrome screening in early pregnancy. The sensitivity is > 99%. However, when used for screening of younger women without risk factors, the positive predictive value is < 50%, i.e. a suspicion of Down syndrome based on NIPT must be confirmed by an invasive diagnostic test such as chorionic villus sampling (CVS). Furthermore, when offered to women with risk factors such as low plasma levels of pregnancy associated plasma protein A or increased fetal nuchal translucency, NIPT misses about one-third of the pathogenic copy number variants, which can be detected by high-resolution chromosomal microarray after CVS (Vogel et al. Ultrasound Obstet Gynecol 2017; Epub ahead of print). It is important and challenging to communicate these figures to pregnant women who are considering NIPT. Disparities between clinics with regard to the content of this counselling probably explains the huge differences in the uptake of NIPT at the expense of CVS. In some clinics, < 15% of the women with risk factors opt for NIPT, whereas this figure is > 80% at other clinics. Another NIPT limitation is the proportion of 'no-call' results, i.e. the NIPT fails to return a result in 1–3% of women. The most common cause for this is an insufficient cffDNA fraction, often associated with an increased maternal body mass index. Most probably, women with an increased body mass index have an enhanced turnover of adipocytes and, consequently, an increased level of cell-free maternal DNA, which dilutes the cffDNA resulting in a low cffDNA fraction. However, this may not be the only cause of 'no-call'. Chan et al. present results of a retrospective study showing that, as compared with the background population, women with 'no-call' are at increased risk of chromosomal aneuploidies (6.5 versus 0.2%), pre-eclampsia (11 versus 1.5%) and gestational diabetes (23 versus 7.5%). Even though these findings need to be confirmed in more studies, it makes sense to already take the results into consideration in our daily practice Therefore, 'no-call' women should be offered not only a repeat NIPT but also a CVS (indeed, a 'no-call' could be classified as a risk marker in itself). We should also ensure that such women receive counselling regarding the risk of pre-eclampsia (with possible prevention with acetylsalicylic acid) and gestational diabetes with a focus on prevention by modification of lifestyle and an oral glucose tolerance test for timely diagnosis. Previous studies have demonstrated that women with abnormally low as well as abnormally high cffDNA levels in the second trimester of pregnancy are at increased risk of developing pre-eclampsia (Jakobsen et al. Transfusion 2013;53:1956–64). Most probably, this association also explains why women with 'no-call' NIPT in the first trimester are at increased risk of adverse obstetric outcome. However, we need more studies to explain this association, including studies that might give us knowledge about pathways leading to adverse obstetric outcomes. Full disclosure of interests available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.