ACMG recommendations on non-invasive prenatal 'screening'

Philippa Brice

12 April 2013

The American College of Medical Genetics and Genomics (ACMG) has released a new policy statement on what it terms non-invasive prenatal screening (NIPS), published in the journal Genetics in Medicine.

Most commonly referred to as non-invasive prenatal diagnosis (NIPD), this refers to new techniques that can selectively analyse fetal DNA or RNA extracted from the mother’s blood, allowing much earlier and safer testing than invasive techniques (see lecture on NIPD by inventor Dennis Lo for more information). However, such testing is not 100% accurate in all cases and may (like many prenatal tests) result in false-positive or false-negative results, so the ACMG have decided to refer to it as screening. In the UK, the technique is now often referred to as non-invasive prenatal testing (NIPT), since it is considered a form of testing even if it is not completely diagnostic.

The new ACMG statement is broadly supportive of NIPT, acknowledging that it has effectively ‘arrived’ now that there are multiple commercial offerings available in the US. Providers include Sequenom, Natera, Ariosa Diagnostics and Verinata (Illumina); these all test for Down Syndrome (trisomy 21) and typically also for other common aneuploidies such as trisomy 13 (Patau Syndrome) and trisomy 18 (Edward’s Syndrome). The advantages of such tests over other standard prenatal screening approaches for the same conditions are noted, but the ACMG calls for providers to give ‘the most clinically relevant metrics’ ie. positive predictive value (PPV) and negative predictive value (NPV) for their tests. This would certainly make it much easier to compare the performance of different tests. 

The statement also outlines the limitations of such testing, which is only for specific indications and provides limited information – for example, it does not detect many other chromosomal abnormalities. The ACMG therefore recommends that positive results for NIPT should be confirmed by standard invasive means (amniocentesis or chorionic villus sampling) followed by microarray analysis, preceded by suitable counselling for the pregnant women. This seems a sensible approach and one likely to be followed in the UK; non-invasive testing offers a superior approach for screening for selected disorders (whether among high-risk patients or the entire pregnant population, an issue still open to debate), but cannot replace all aspects of antenatal screening (eg. ultrasound scanning for fetal anomalies) or definitive diagnosis for aneuploidies.

The lead author of the ACMG policy statement, Dr Anthony R. Gregg, has stressed the need for clinicians to provide suitable counselling “with the goal of avoiding patient harm or confusion”. This ought to include the provision of suitable information to allow women to make a properly informed choice about accepting or declining testing.

Looking ahead, the ACMG envisions a future where whole-genome or exome sequencing of fetal DNA might become routine, but is an entirely different scenario and seems a long way (and a whole host of ethical debates) off. Technical barriers aside, screening normally aims to identify a specified set of conditions, whereas large scale sequencing generates a vast amount of data that requires expert analysis and interpretation and typically identifies multiple variants of uncertain pathological significance – not a desirable or practical situation within antenatal care.

Overall however, the statement reflects a generally positive but suitably cautious approach to the use of this exciting technology.

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