Table 9.9First- and second-trimester screening for Down’s syndrome only

StudyMalone et al. (2005)785Wald et al. (2003)316Knight et al. (2005)786Platt et al. (2005)787
Type of studyProspective cohortNested case–control (within a cohort)Prospective cohortProspective cohort
Year of publication2005200320052004
Period1999–20021996–20012001–2003Not specified
Setting15 medical centres, USA25 maternity centres, UK and Austria229/260 prenatal care practitioners, USA12 prenatal diagnostic centres, USA
Study populationUnselectedUnselectedSelected (61% enrolled for study)Selected (low uptake of second-trimester screening) (small sample)
ExclusionsAdequately describedAdequately describedAdequately describedAdequately described
Test conductedAll serum tests with NT
(combined, quadruple, integrated and serum integrated)
All serum and urine biochemical markers with NTIntegrated serum screeningSequential screening using triple marker after first-trimester combined test
Monitoring of test qualityAdequateAdequate, double blindingAdequateAdequate
Validated reference standardYes (prenatal karyotype, pregnancy records)Yes (karyotype-pre/postnatal, pregnancy records)Yes (prenatal karyotype, pregnancy records)Yes (karyotype-prenatal, pregnancy records)
Sample size (% of study population)33 547 (88.2%) with complete data from both trimesters43 712 (92%)
98 cases, 490 controls for screening performance; 600 controls added for statistical power
8773 (78.6%)4325 (52.7%)
first-trimester screen-positive 180
first-trimester screen-negative 4145
Maternal ageMean 30.1 years, SD 5.8 yearsNot specified
Median: 29 years
Mean 27.8 years, SD 5.5 yearsMean 34.5 years, SD 4.6 years
Number of cases (prevalence)92 (0.27%)101 (0.23%)16 (0.18%)13 (0.30%)
Estimated detection rate at fixed FPR 5% (95% CI):
combined (11 weeks): 87% (82–92%)
quadruple (15–17 weeks): 81% (70–86%)
serum integrated: 88% (81–92%)
fully integrated: 96% (92–97%)
Estimated detection rate at fixed FPR 5%:
first trimester (10–13 weeks): PAPP-A + NT 76%; combined 84%; combined + inhibin A 87%
second trimester (15–20): double 71%; triple 77%; quadruple 83%
Integrated screening (both first and second trimester): NT (10 weeks) + quadruple 90%; serum integrated 90%; integrated 93%
Observed screening performance with 95% CI:
triple: risk 1 : 270; DR 67% (43–84%); FPR 6.4% (5.9–6.9%)
quadruple: risk 1 : 150; DR 56% (33–76%); FPR 3.3% (2.9–3.7%)
serum integrated: risk 1 : 100; DR 79% (55–92%); FPR 3.2% (2.8–3.6%)
Observed screening performance with 95% CI among first-trimester screen-negative women:
risk 1 : 270; DR 85.7% (42.1–99.6%); FPR 8.9% (8.0–9.8%)
Evidence levelIbIIIIII
CommentsThe observed performance characteristics were:
First-trimester combined screening with risk cut-off 1 : 300 – DR 82% with FPR 5.6%
Second-trimester quadruple screening with risk cut-off 1 : 100 DR 85% with FPR 8.5%
Sequential screening in both the trimesters – DR 94% with FPR 11%
Note: The DR is subject to bias as the study excluded fetuses with hygroma which might have aborted spontaneously when most of the Down’s syndrome cases were ascertained.
Screening performance was also evaluated for NT and all serum and urine markers individually.
For NT – Failure to obtain satisfactory NT image was lowest (14%) at 11 weeks, and highest (19%) at 10 and 13 weeks.
Success rate increased with sonographer experience – 86% with = 400 images VS 81% with < 200 images experience.
For urine markers – Invasive Trophoblastic Antigen (ITA) was the best marker and only discriminatory in second trimester. On combining with Quadruple Test, FPR was decreased from 6.2 to 4.2%, and with Integrated test from 0.9 to 0.6% (both tests at fixed DR of 85%).
The study also evaluated the safety and cost-effectiveness of various markers. Safety will be discussed separately under effectiveness.
The study population was the same as that of Wapner et al.(2003)769 (described in First-trimester screening for Down’s syndrome and other chromosomal anomalies). After undergoing Combined test in the first trimester, risks were disclosed to the women. Triple test was offered to all screen-negative women and those screen-positive women who decided not to undergo diagnostic tests after the first-trimester positive test.

DR = detection rate; DS = Down’s syndrome; FPR = false positive rate; NT = nuchal translucency; PAPP-A = pregnancy-associated plasma protein-A; SD = standard deviation;.

From: 9, Screening for fetal anomalies

Cover of Antenatal Care
Antenatal Care: Routine Care for the Healthy Pregnant Woman.
NICE Clinical Guidelines, No. 62.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2008 Mar.
Copyright © 2008, National Collaborating Centre for Women’s and Children’s Health.

No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK []. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore for general use.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.