Antenatal ‘reflex’ DNA screening for Down’s syndrome

We described the history of using baby’s cell-free DNA fragments in mother’s blood to identify Down’s syndrome in a news item on 22 October 2008, and reported a successful large multicentre study of the method in women undergoing a routine first trimester combined antenatal screen in a news item on 23 April 2015. The authors of the latter study found that the false positive rate of DNA testing was far lower than that of standard screening, so fewer invasive tests to examine baby’s cells directly (amniocentesis or chorionic villus sampling) would have been performed to detect each case. However, they noted that the routine first trimester combined screen can identify risk for abnormalities not detectable by DNA testing and DNA testing is expensive. A generally adopted approach has been to continue to offer women the combined screen between weeks 11 and 13; those whose results indicate a risk greater than 1 in 150 are then invited to discuss whether they wish to proceed either to an invasive test or to have a blood sample taken to examine the baby’s DNA.

A report published online on 9 November 2017 in the journal Genetics in Medicine assessed the use of ‘reflex’ DNA screening. A second blood sample was taken at the routine first trimester screen and the plasma stored until the routine results were known. ‘Reflex’ examination of baby’s cell-free DNA in that sample was carried out if the combined risk of abnormality was high.

Five NHS obstetric units screened 22,812 pregnancies, of which 106 were abnormal. ‘Reflex’ DNA testing was carried out on the second specimens of the 2,480 (10.9%) whose routine antenatal screens showed a combined risk for Down’s, Edwards or Patau syndrome greater than 1 in 800. Of these, 101 had a positive test, so detecting  95% of the 106 abnormal pregnancies in the whole group. There were only four false positive DNA results, 0.02% of the whole group, compared with 2.42% with the routine test. The report said that no other method of prenatal screening for these disorders has such a high detection rate for such a low false-positive rate. The odds of being affected given a positive result were 25:1.

The project was led by Professor Sir Nicholas Wald from the Wolfson Institute of Preventive Medicine, Queen Mary University of London. He said "The reflex DNA approach has beneficial resource implications by reducing the number of women who need counselling on account of a positive screening result, and by avoiding about five out of six diagnostic amniocenteses that would otherwise be indicated. The extra costs of the DNA tests are offset against savings from fewer amniocenteses and associated counselling."