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. 2017 Mar 15;2017(3):CD012599. doi: 10.1002/14651858.CD012599

Wald 2003b.

Clinical features and settings Routine screening
Participants 606 participants: 101 cases, 505 controls matched for gestation, duration of storage and centre
UK and Austria ‐ multi‐centre trial
September 1996 to April 2000
Pregnant women
9‐13 and 14‐20 weeks' gestation
Study design Case‐control study
Target condition and reference standard(s) Down's syndrome: 101 cases
Rerence standards: invasive testing (following second trimester screening) or follow‐up to birth
Index and comparator tests First trimester NT (midsagittal section, optimal magnification of thickness of translucent space between inner skin surface and fascia covering cervical spine (white black interface (outer) ‐ black white interface (inner), 41 models of ultrasound machine, 20 minutes allotted scanning time)
First trimester and second trimester serum AFP, hCG, UE3, PAPPA, free ßhCG (time resolved fluoroimmunoassay, AutoDELFIA)
First trimester and second trimester inhibin A (Sandwich enzyme linked immunosorbent assay, Oxford Bioinnovation)
First trimester and second trimester urinary beta core fragment, total‐hCG, ITA and free ßhCG (ITA and beta core fragment, Quest diagnostics USA)
Follow‐up Follow‐up by: 1) Staff at local hospitals completed a study outcome form at, or just after. delivery, 2) Study records of CVS, amniocentesis or karyotype at birth linked to information from cytogenic laboratories, 3) Study records linked to records of cases of Down's syndrome from the National Down's Syndrome Cytogenetic Register, 4) Information obtained from local obstetrical outcome records, 5) Forms sent to all women with a request to return details of the outcome of their pregnancy, 6) Individual searches in respect of women whose outcomes of pregnancy had not been obtained by any of the previous methods. 96% Birth/Karyotype full outcome documentation obtained
Aim of study To identify the most effective, safe and cost effective strategy for antenatal screening for Down's syndrome using NT, maternal serum and urine markers in the first and second trimesters of pregnancy and maternal age in various combinations
Test characteristics  
Reference standard used  
Notes Performance of screening assessed at 17 weeks' gestation. Study tried to be non‐interventional in the first trimester ‐ second trimester testing was aimed to be used as the basis for any referral for invasive testing
Table of Methodological Quality
Item Authors' judgement Description
Representative spectrum? 
 All tests Yes Routine screening of typical pregnant population
Acceptable reference standard? 
 All tests Yes Karyotyping or follow‐up to birth
Partial verification avoided? 
 All tests Unclear 4% of total patient cohort did not have a documented outcome of pregnancy. Unclear if any of these included in nested case‐control study
Differential verification avoided? 
 All tests No Choice of reference standard depended on index test results
Incorporation avoided? 
 All tests Yes Reference standard was independent of the index test
Reference standard results blinded? 
 All tests No Reference standard interpreted with knowledge of index test results
Index test results blinded? 
 All tests Yes Index test interpreted without knowledge of reference standard results
Relevant clinical information? 
 All tests Yes Information available as would be in standard clinical practice
Uninterpretable results reported? 
 All tests Yes Rates of NT failure on average 9%. Pre‐10 weeks' gestation, > 33% failure rate, declined to 7% at 12 weeks
Withdrawals explained? 
 All tests No No details of withdrawals given