Prenatal reflex DNA screening for trisomies 21, 18, and 13

Abstract

Purpose: The purpose of the study was to determine the screening performance of prenatal reflex DNA screening for trisomies 21 (T21), 18 (T18), and 13 (T13) as part of a routine service at five hospitals.Methods: Women who accepted screening had a first-trimester combined test (pregnancy-associated plasma protein A, free β-human chorionic gonadotropin, nuchal translucency interpreted with maternal age). Those with a risk of having an affected pregnancy ≥ 1 in 800 were reflexed to a DNA sequencing test using stored plasma from the original blood sample, thereby avoiding the need to recall them.Results: Of 22,812 women screened (including 106 with affected pregnancies), 2,480 (10.9%) were reflexed to DNA testing; 101/106 were detected (69/73 T21, 24/25 T18, and 8/8 T13), a 95% detection rate (95% confidence interval 89-98%) with four false positives (0.02%, 95% confidence interval 0.00-0.05%). The odds of being affected given a positive result were 25:1. Of the 105 screen-positive pregnancies, 91 (87%) had an invasive diagnostic test. Reflex DNA screening avoided up to 530 invasive diagnostic tests compared with using the combined test.Conclusion: Reflex DNA screening was successfully implemented in routine care, achieving a high detection rate, low false-positive rate, and, consequently, greater safety with fewer invasive diagnostic tests than other methods of screening.

Prenatal screening for Down syndrome in twin pregnancies: Estimates of screening performance based on 61 affected and 7302 unaffected twin pregnancies

“…Screening performance in twin pregnancies was compared with that in singleton pregnancies using updated parameters from the Serum, Urine, and Ultrasound Screening Study (SURUSS) with a revised standard deviation for NT in unaffected pregnancies to take account of improvements in measuring NT over time, leading to decreases in the standard deviation of the log NT MoM values. The revised NT standard deviation was based on data from an audit of reflex DNA screening for Down syndrome, trisomy 18 and trisomy 13; among 22 706 unaffected pregnancies, the log 10 standard deviation was 0.0963 in pregnancies screened in the 11th week of pregnancy and 0.0843 between 12 and 13 weeks, lower than the values we previously reported (0.1275 and 0.1105, respectively) . The lower standard deviation of 0.0843 was used in estimating screening performance in singleton pregnancies.…”

Response to Wald et al

“…To the Editor: I would like to thank Professor Wald and his team 1 for their article adding to the evidence base for the prenatal analysis of plasma DNA, also called noninvasive prenatal testing in the UK or screening (NIPT or NIPS), to screen for trisomies 21,18, and 13. NIPS has previously been shown to be a superior test compared with combined screening methods involving serum markers and ultrasound scanning.…”

“…This is described as "contingent" testing in the paper by Wald et al 1 and is compared with their preferred "reflex" testing model. Both models use plasma-free DNA technology, but in the reflex pathway blood is taken at the first-stage appointment and is tested only when results from this stage are known and a pregnancy with a high chance of being affected by a trisomy is identified.…”

“…2 In the context of a contingent versus a reflex model, the authors cite a report that 18% of women recalled after the first stage in a contingent model proceeded straight to diagnostic testing at the risk of increasing the number of diagnostic tests and the falsepositive rate when compared with reflex testing. 1 A different framing is that after the first stage in the contingent model, parents were free to decline to consent to NIPS and opt for the certainty of a diagnostic procedure. Nearly a fifth of parents chose this route.…”

Conflating screening detection rates with the uptake of further testing: A potential source of confusion

“…The comparison is based on 400,000 women screened (similar to the number screened in England and Wales each year) and test detection rates previously reported. 3 Method 1 uses the combined test alone: 518 pregnancies are screen positive out of 640 affected pregnancies. Of these, 50% take up the offer of invasive diagnostic test, which identifies and diagnoses 259 affected pregnancies.…”