Cross-trimester marker ratios in prenatal screening for Down syndrome.
OBJECTIVE
To examine the performance of Integrated Down syndrome screening (first- and second-trimester measurements integrated into a single screening test) when ratios of the levels of the same serum markers measured in both these trimesters (cross-trimester ratios) are added as new screening markers.


METHODS
Using data from Serum Urine and Ultrasound Screening Study (SURUSS), second-trimester concentrations (in multiples of the median, or MoM) of pregnancy associated plasma protein A (PAPP-A), alphafetoprotein (AFP), unconjugated oestriol (uE(3)), human chorionic gonadotrophin (hCG) (free beta and total), and inhibin-A were divided by the first-trimester concentration to obtain a cross-trimester (CT) ratio for each analyte in 74 Down syndrome and 492 unaffected pregnancies. We identified CT ratios that improved screening performance and then, using Monte Carlo simulations, estimated the efficacy and cost effectiveness of adding them to the Integrated and serum Integrated tests.


RESULTS
All the median CT ratios differed significantly between Down syndrome and unaffected pregnancies. Setting the Integrated test to achieve a 90% detection rate, the false-positive rate (FPR) was 0.7% with CT ratios for PAPP-A, uE(3), inhibin-A, and total hCG compared with 2.2% without CT ratios, a reduction of about two-thirds. Using the serum Integrated test to achieve the same 90% detection rate and the first-trimester measurements made at 11 completed weeks of pregnancy, the corresponding FPRs were 2.4 and 8.1%, a similar proportional reduction. The AFP CT ratio had little effect on screening performance. Using CT ratios did not increase the cost per Down syndrome pregnancy detected.


CONCLUSIONS
The addition of CT ratios to an Integrated test substantially improves the efficacy and safety of prenatal screening for Down syndrome. It is cost effective and could be usefully introduced into screening programmes.
Wald
Nicholas J
NJ
Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, UK. n.j.wald@qmul.ac.uk
Bestwick
Jonathan P
JP
Morris
Joan K
JK
D015415:Biomarkers; D004314:Down Syndrome / Q000175:diagnosis* / Q000191:economics / Q000196:embryology*; D005189:False Positive Reactions; D005260:Female; D005865:Gestational Age; D006801:Humans; D011237:Predictive Value of Tests; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood / Q000652:urine; D011262:Pregnancy Trimester, Second / Q000097:blood / Q000652:urine; D011296:Prenatal Diagnosis / Q000191:economics / Q000379:methods*
D015415:Biomarkers