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Editor’s comment: Prof. Yves Ville: To know the chance, a chance to know

(Editor’s comment relates to the 3 AJOG articles below: Biggio Jr., Shani et al & Norton et al)

Advanced screening for fetal aneuploidies using fetal DNA in maternal blood represents a major technical breakthrough that is still struggling to find a pragmatic place within the screening algorithms in most countries, after 4 years of clinical use. The wide and sometimes wild dissemination of the test stresses the critical need for the prescribers of the test to understand the difficulties of its interpretation.

Three papers published in the June issue of AJOG contribute to this much needed endeavour :

JR Biggio elegantly reviews 4 years of clinical use of fetal DNA testing and puts advantages and pitfalls in perspective. Shani et al highlights which chromosomal defects escape fetal DNA testing, coming up to around 50% of all chromosomal abnormalities diagnosed in the context of prenatal diagnosis. Finally the range of differences in screening performance between cell-free DNA and conventional approaches, can usefully be approached by large prospective study cohort studies in the general obstetric population, such as that published this month by Norton et al.

Briefly :

- The test failures in 1-5% of cases identifies a group that is at higher risk of abnormal karyotype.

- Fetal DNA testing is based on a predetermined risk threshold which will therefore determine a false positive rate that will be all the more important that we want to reduce the risk of false negative results.

- Combined first trimester screening based on the combination of the value of ultrasound and the dosage of serum markers and maternal age for, allows the identification of chromosomal abnormalities other than trisomy 21 in 20 to 30% of cases and these escape fetal DNA testing. Fetal DNA testing has also a reduced sensitivity for trisomy 18 and trisomy 13

- A decline in the quality of first trimester ultrasound in the context of fetal DNA testing is unfortunately a realistic prospect and this could cause delay or failure to diagnose defects or syndromes whose direct or indirect ultrasound features in the first quarter of pregnancy will be ignored.

- The fraction of fetal DNA in the total circulating maternal DNA emerges as a key factor in the performance of fetal DNA testing. This fraction is between 4% and 20% and the impact of this rate is that the decrease of the risk factor by a negative DNA testing is that only x1 / 3 for the lowest proportions of fetal DNA and up to more than 1/10 000 for the highest values ​. A concrete example for an a priori risk of 1/20 with a negative DNA testing : This could bring a risk <1 / 10 000 whereas if the fetal fraction is only 5%, the risk is in fact still of 1/160!

- Similarly the initial risk as assessed by the combined first trimester screening is an element whose importance is considerable. The lower the initial risk, the higher the negative likelihood ratio following negative DNA testing. (x 1/100 to x1 / 10,000). However, if the risk is between 1/10 and ½, the reassurance is only x1 / 1000 to

Finally, recent studies on the risk of miscarriage after amniocentesis and chorionic villus sampling are 0.1 to 0.2% and molecular cytogenetics allows the array CGH technique to diagnose chromosomal structure reshuffling of under a megabase.

All these and more should be known by prescribers of the test and they should be able to explain these issues in plain language to their patients as part of a fair counselling.

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Commentaries by Editor Prof. Jim Thornton