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. 2017 Mar 15;2017(3):CD012600. doi: 10.1002/14651858.CD012600

3. Summary of study characteristics.

Study NT, PAPP‐A, free ßhCG and age Nasal bone NT and age NT Maternal age (range) in years Reference standard Population Study design Study location
Acacio 2001       X Mean 35.8 (21‐45) CVS biopsy, amniocentesis or blood or placenta used for fetal karyotyping High‐risk referral for invasive testing Retrospective study of patient notes South America
Audibert 2001     X   Mean 30.1, all < 38, 86% < 35, 14% ≥ 35 Prenatal karyotype conducted (in 7.6% of patients) depending on presence of risk > 125, high maternal age, parental anxiety, history of chromosomal defects or parental translocation or abnormal second trimester scan age Routine screening Prospective consecutive series France
Babbur 2005       X Median 37 (19‐46) Invasive testing offered to women with NT > 3 mm or risk > 1:250 as defined by combined NT and serum results (CVS from 11 weeks, amniocentesis from 15 weeks). Rapid in situ hybridisation test in patients with risk > 1:30. No details given of any follow‐up to birth Women requesting screening (self‐paying service) and women attending on account of previous pregnancy history of fetal abnormality Prospective cohort UK
Barrett 2008 X       Mean 34.9 for screen positives, 30.5 for screen negatives Karyotyping or follow‐up to birth Routine screening Cohort Australia
Belics 2011         Mean 36.4 (15‐46) for Down's cases, 29.8 (15‐49) for unaffected pregnancies Amniocentesis or CVS (85% of women) or follow‐up to birth High‐risk referral for invasive testing Cohort Budapest
Benattar 1999     X   Mean 32 (16‐46), 8.3% > 35 Amniocentesis due to maternal age > 38 years (6.1% or women). Karyotyping encouraged for women with positive result on one or more index test. No details of reference standard for index test negative women Routine screening Prospective cohort France
Bestwick 2010 X   X X Median 39 for Down's cases, 34 for unaffected pregnancies Karyotyping or follow‐up to birth Routine screening Retrospective cohort UK
Biagiotti 1998 X   X   Unclear (maybe all ≥ 38) Amniocentesis or CVS High‐risk referral for invasive testing Case control Italy
Borenstein 2008         Median 35 (17‐49) CVS High‐risk referral for invasive testing Prospective cohort UK
Borrell 2005 X   X   Not reported CVS (high‐risk women) or follow‐up to birth Routine screening Retrospective cohort Spain
Borrell 2009 X       Mean 32 Karyotyping or follow‐up to birth Routine screening and high‐risk referral Prospective cohort Spain
Brameld 2008 X       Median 31 (14‐47), 20% ≥ 35 Karyotyping or follow‐up to birth Routine screening Retrospective cohort Australia
Brizot 2001     X   Median 28 (13‐46), 19.4% ≥ 35 Antenatal karyotyping (5.9% of pregnancies: 62% of high‐risk, 29% of medium‐risk and 3% of the low‐risk women). Follow‐up to birth (85.3% of women) Routine screening Prospective cohort Brazil
Centini 2005 X       ≥ 35 (35‐44) Amniocentesis in women high risk on screening (16.2%). Follow‐up at birth in women who were low risk on screening High‐risk patients undergoing routine screening Retrospective cohort Italy
Chasen 2003     X   Median 33 (IQR 31‐36), 36.2% ≥ 35 Karyotyping or follow‐up to birth in 96.1% of patients Routine screening Prospective consecutive cohort USA
Chen 2009         Median 30 (20‐44) for Down's cases, 32 (19‐40) for controls Karyotyping or follow‐up to birth Routine screening Case control China
Christiansen 2005 X       Not reported Karyotyping Screening programmes for syphilis and Down's syndrome Case control Denmark
Christiansen 2009 X       Median 37.5 for Down's cases, 36.4 for controls Karyotyping or follow‐up to birth Routine screening Case control Denmark
Christiansen 2010 X       Median 36 (25‐44) for Down's cases, 29 (17‐45) for controls Karyotyping or follow‐up to birth Routine screening Case control Denmark
Cicero 2004a         Median 37 (16‐48) CVS High‐risk referral for invasive testing Prospective cohort USA
Cicero 2006   X     Median 35 (18‐50) CVS or amniocentesis (in high risk women) or follow‐up to birth Routine screening Prospective cohort UK
Cocciolone 2008 (first trimester screening cohort) X       Median 31.3 Karyotyping or follow‐up to birth Routine screening Cohort Australia
Cowans 2009 X       Mean 38 (16‐49) for Down's cases, 29 (13‐56) for unaffected pregnancies Karyotyping or follow‐up to birth Routine screening Cohort UK
Cowans 2010 X       Mean 37.0 (IQR 32.9‐40.5) for Down's cases, 32.4 (IQR 29.0‐35.9) for controls Karyotyping or follow‐up to birth Routine screening Case control UK
Crossley 2002 X   X   Median 29.9, 15.4% ≥ 35 CVS (offered where women had high NT measurements), amniocentesis or follow‐up to birth Routine screening Prospective cohort UK
De Graaf 1999 X   X   Not reported CVS and amniocentesis High‐risk referral for invasive testing Case control Netherlands
Ekelund 2008 X       Not reported Karyotyping or follow‐up to birth Routine screening Cohort Denmark
Gasiorek‐Wiens 2001     X   Median 33 (15‐49), 36.1% > 35 CVS, amniocentesis or follow‐up to birth Routine screening Prospective cohort Germany, Switzerland and Austria
Gasiorek‐Wiens 2010     X   Median 35.1 (13.2‐46.7) Karyotyping or follow‐up to birth Routine screening Cohort Germany
Go 2005 X       49% ≤ 35, 51% ≥ 36 Invasive testing or follow‐up to birth Routine screening Retrospective cohort Netherlands
Gyselaers 2005 X   X   Not reported CVS, amniocentesis or follow‐up to birth Routine screening Prospective cohort Belgium
Habayeb 2010         Median 35.4 (18‐49) Karyotyping or follow‐up to birth Routine screening Cohort UK
Hadlow 2005* X       Mean 30.7, 21.2% ≥ 35 CVS, amniocentesis or follow‐up to birth Routine screening Prospective cohort Australia
Hafner 1998*       X Median 28 (15‐49) 6.9% ≥ 35 Amniocentesis or CVS in patients with previous Down’s pregnancy, > 35 years or with a positive biochemical test result. Other women underwent scan at 22 weeks and, if NT >2.5 mm special examination directed to examination of fetal heart. Follow‐up to birth Routine screening Prospective cohort Austria
Has 2008 X X X   Median 28.3 (17‐45) Karyotyping or follow‐up to birth Routine screening Cohort Turkey
Hewitt 1996       X Median 37 (21‐48) CVS High‐risk referral for invasive testing Prospective cohort Australia
Hormansdorfer 2011 X       Mean 31.1 (16‐46), 22% ≥ 35 Karyotyping or follow‐up to birth Routine screening Prospective cohort Germany
Huang 2010 X       Median 30 (15‐47), mean 29.8 (SD 3.3) Karyotyping or follow‐up to birth Routine screening Cohort Taiwan
Jaques 2007 X       Mean 33 (16‐51), 18.5% ≥ 37 Karyotyping or follow‐up to birth Routine screening Retrospective cohort Australia
Jaques 2010 FTS (first trimester screening) X       Mean 16.3% ≥ 37 Karyotyping or follow‐up to birth Routine screening Retrospective cohort Australia
Kagan 2010 X   X   Mean 35.4 (14.1‐52.2) Karyotyping or follow‐up to birth Routine screening Prospective cohort UK
Kim 2006       X Mean 29.9 (SD 3.3) Amniocentesis or CVS in patients considered high risk (NT > 2.5, aged > 35 years, positive biochemical test result, history or chromosomal abnormality, fetal structural abnormality at ultrasound or other reason). Follow‐up to birth Routine screening Retrospective cohort South Korea
Koster 2011 X       Median 37 (IQR 36‐39) Karyotyping or follow‐up to birth Routine screening Case control Netherlands
Kozlowski 2007 GC (Gynaecologists' practices) X   X   Median 32 (15‐48), 26.4% ≥ 35 Karyotyping or follow‐up to birth Routine screening Cohort Germany
Kozlowski 2007 PC (Prenatal centre) X   X   Median 34 (14‐46), 43.2% ≥ 35 Karyotyping or follow‐up to birth Routine screening Cohort Germany
Krantz 2000* X   X   34.7% ≥ 35 Not reported Routine screening Prospective cohort USA
Kublickas 2009 X       51% ≥ 35 Karyotyping or follow‐up to birth Routine screening Prospective cohort Sweden
Kuc 2010 X       Not reported Karyotyping or follow‐up to birth Routine screening Case control Netherlands
Lam 2002     X   Mean 30.5 (19% ≥ 35) for unaffected pregnancies Women considered high risk offered CVS (0.7%) or amniocentesis (11.8%).
 
 Follow‐up to birth Routine screening Prospective cohort Hong Kong
Leung 2009 X X     Median 32 (IQR 30‐35), 27.4% ≥ 35 Amniocentesis or follow‐up to birth Routine screening Prospective cohort China
MacRae 2008     X   Not reported Karyotyping or follow‐up to birth Routine screening Retrospective cohort UK
Maiz 2007         Median 35 (17‐49) CVS High‐risk referral for invasive testing Prospective cohort UK
Maiz 2009         Median 34.5 (14.1‐50.1) Karyotyping or follow‐up to birth Routine screening Prospective cohort UK
Malone 2004   X     Mean 30.1 (16‐47), 22.1% ≥ 35 Amniocentesis (in women considered high risk, n = 510) or follow‐up to birth Routine screening Prospective cohort USA
Malone 2005 X       21.6% ≥ 35 Amniocentesis offered to women with positive results from any screening test. Follow‐up to birth Routine screening Prospective cohort USA
Marchini 2010* X       Median 31.3 (18‐45), 19.7% ≥ 35 Karyotyping or follow‐up to birth Routine screening Retrospective cohort Italy
Marsis 2004       X Mean 37.8 (35‐43) Amniocentesis (unclear in which patients this was conducted) or follow‐up to birth Screening of patients ≥ 35 years of age Prospective cohort Indonesia
Marsk 2006 X   X   Mean 38.5 (SD 4.0) for Down's cases, 35.5 (SD 4.0) for controls Not reported Routine screening Case control Sweden
Matias 1998         Median 35 (17‐46) Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks High‐risk referral for invasive testing Prospective cohort UK and Portugal
Matias 2001         Median 35 (17‐46) Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks High‐risk referral for invasive testing Prospective cohort Portugal
Mavrides 2002     X   Median 35 (15‐42) CVS or follow‐up High‐risk referral for invasive testing Prospective cohort UK
Maxwell 2011 FTS (first trimester screening cohort) X       Median 31 (14‐48), 24.3% ≥ 35 Karyotyping or follow‐up to birth Routine screening Prospective cohort Australia
Maymon 2005         Mean 33.7 (SD 4.9) for Down's cases, 30.3 (SD 4.5) for controls Amniocentesis (recommended for women with higher risk on first or second trimester testing) or follow‐up to birth Routine screening Case control Israel
Maymon 2008 X   X   Not reported Karyotyping or follow‐up to birth Routine screening Case control USA
Merz 2011 X       Not reported Karyotyping or follow‐up to birth Routine screening Retrospective cohort Germany
Michailidis 2001       X Mean 30.1 (13‐50), 21.1% ≥ 35, 11.9% ≥ 37 Karyotyping in women considered at risk due to index test results, age or family history or those with considerable anxiety (632 women, 8.5%) or follow‐up to birth Routine screening Prospective cohort UK
Molina 2010 high risk (High‐risk cohort)   X     Mean 32.7 (16.7‐47.5) CVS High‐risk referral for invasive testing Cohort Spain
Molina 2010 screening (Screening cohort) X       Not reported Karyotyping or follow‐up to birth Routine screening Cohort Spain
Monni 2005     X   Median 32 (14‐49) Karyotyping or follow‐up to birth Routine screening Prospective cohort Italy
Montalvo 2005 X       Mean 31.1 (14‐49), 25.9% ≥35 Invasive testing offered to women considered high risk from screening results or follow‐up to birth Routine screening Prospective cohort Spain
Moon 2007   X     Mean 35.5 (SD 4.8) for Down's cases, 31.7 (SD 3.4) for unaffected pregnancies Karyotyping or follow‐up to birth Routine screening Prospective cohort Korea
Muller 2003 X   X   Not reported Invasive testing (offered to women with high NT measurement) or follow‐up to birth Routine screening Retrospective cohort France
Nicolaides 1992       X Median 38 (22‐47) Fetal karyotyping by amniocentesis (52%) or CVS (48%) High‐risk referral for invasive testing Prospective cohort UK
Nicolaides 2005 X       Median 31 (13‐49) Amniocentesis or CVS (patients considered high risk based on screening). First trimester presence/absence of nasal bone, presence/absence of tricuspid regurgitation or normal/abnormal Doppler studies (patients of intermediate risk on first trimester screening and did not undergo CVS or amniocentesis. With the addition of information from these tests, if adjusted risk was high, CVS was performed). Follow‐up to birth Routine screening Prospective cohort UK
Niemimaa 2001 X   X   17.5% ≥ 35 Invasive testing (patients considered high risk based on NT screening) or follow‐up to birth. Routine screening Prospective cohort Finland
Noble 1995         Median 34 (15‐47), 47% ≥ 35 Karyotyping performed (27% of women) due to increased NT (14%), advanced maternal age (10%), previous chromosomally abnormal child (0.5%) or parental anxiety (2%).
 Ultrasound examination at 20 weeks (65% of patients). Follow‐up to birth (9% of women) Routine screening in a high risk population Prospective cohort UK
O'Callaghan 2000     X   Median 32 CVS, amniocentesis or neonatal karyotyping or follow‐up to birth Routine screening Prospective cohort Australia
O'Leary 2006 X   X   Median 31 (14‐47), 20% ≥ 35 CVS or amniocentesis (women assessed to be high risk on screening) or follow‐up to birth Routine screening Prospective cohort Australia
Okun 2008 FTS (first trimester screening cohort) X       Mean 34 Karyotyping or follow‐up to birth Routine screening Prospective cohort Canada
Orlandi 1997 X   X   Range 15 to 46, 35% ≥ 35 Not reported Routine screening Prospective cohort Italy
Orlandi 2003   X     Median 31.7 (SD 4.0) for Down's cases, 36.5 (SD 4.1) for unaffected pregnancies CVS or amniocentesis (women considered high risk on screening on the basis of NT and biochemical results, but not on nasal bone screening, or if requested due to age or anxiety) or follow‐up to birth Routine screening (2 centres) or in referred patients (1 centre) Prospective cohort Italy and Netherlands
Orlandi 2005   X     Median 30.5 (SD 8.2) Not reported Routine screening Retrospective cohort Italy
Otaño 2002   X     Median 36 (19‐44) CVS High‐risk referral for invasive testing Prospective cohort Argentina
Pajkrt 1998     X   Mean 31.4 (SD 5.7), 24% ≥ 35 Prenatal karyotyping offered to patients considered high risk or maternal anxiety (conducted in 24%) or follow‐up to birth Routine screening Prospective cohort Netherlands
Pajkrt 1998a       X Mean 37.6 (22‐46) Prenatal karyotyping High‐risk referral for invasive testing Consecutive cohort Netherlands
Palomaki 2007 FTS (first trimester screening cohort)         Mean 32.3 (SD 4.6) Karyotyping or follow‐up to birth Routine screening Prospective cohort Canada
Perni 2006 X       Median 33.0 (IQR 31.0‐36.0) CVS or amniocentesis. Cytogenetic testing in cases of miscarriage. Follow‐up to birth. Routine screening Retrospective cohort USA
Prefumo 2005     X   Median 37 (19‐46) CVS High‐risk referral for invasive testing Prospective cohort UK
Prefumo 2006     X   Mean 31.4 (14.5‐50.2) Karyotyping or follow‐up to birth Routine screening Prospective cohort UK
Ramos‐Corpas 2006   X     Mean 30.1 (15‐46) (SD 5.37), 18% ≥ 35 Invasive testing offered to patients considered high risk at screening (> 1:300) or follow‐up to birth Routine screening Prospective cohort Spain
Rissanen 2007 X       29.5, 17.7% ≥35 Karyotyping or follow‐up to birth Routine screening Prospective cohort Finland
Rozenberg 2002     X   Median 30.5 (18‐37) Amniocentesis offered to patients with NT >3mm or serum marker risk was > 1:250, or follow‐up to birth Routine screening Prospective cohort France
Rozenberg 2007 X       Mean 30.9 (SD 4.5) Karyotyping or follow‐up to birth Routine screening Prospective cohort Canada
Sahota 2010 X   X   Median 33.1, 30.1% ≥ 35 Karyotyping or follow‐up to birth Routine screening Prospective cohort China
Salomon 2010 X       Median 30.7 (18.0‐46.3) Karyotyping or follow‐up to birth Routine screening Prospective cohort France
Santiago 2007 X   X   Mean 30.6 (14‐46) Karyotyping or follow‐up to birth Routine screening Retrospective cohort Spain
Sau 2001     X   Mean 28 (SD 5) Invasive testing (women with high risk on screening) or follow‐up to birth Routine screening Prospective cohort UK
Schaelike 2009 X   X   31.0% ≥35 Karyotyping or follow‐up to birth Routine screening Prospective cohort Germany
Schielen 2006* X       Median 36.5 (18‐47) Invasive testing or follow‐up to birth Routine screening Retrospective cohort Netherlands
Schuchter 2001     X   Mean 28 (15‐46), 10.7% ≥ 35 CVS (offered to patients with first trimester NT > 3.5 mm), amniocentesis (offered to patients with first trimester NT 2.5‐3.4 mm, high risk on second trimester serum testing (> 1:250) and those > 35 years) or follow‐up to birth Routine screening Retrospective cohort Austria
Schuchter 2002 X     X 13% > 35 CVS and amniocentesis (offered to patients with increased risk (> 1:400) at first trimester screening. CVS recommended when NT > 3.5 or when women did not want to wait until the 15th week for amniocentesis), or follow‐up to birth Routine screening Prospective cohort Austria
Schwarzler 1999     X   Mean 29.4 (16‐47) Invasive testing (women considered high risk on screening) or follow‐up to birth Routine screening Prospective consecutive cohort UK
Scott 2004 X   X   Median 32 (15‐44), 29% ≥ 35 Invasive testing or follow‐up to birth Routine screening Prospective cohort Australia
Sepulveda 2007   X X   Median 33 (14‐47), 35.4% ≥ 35 CVS, amniocentesis, cordocentesis or follow‐up to birth Routine screening Prospective cohort Chile
Snijders 1998     X   Median 31 (14‐49) CVS and amniocentesis (9.6% of women) or follow‐up to birth Routine screening Prospective cohort UK
Sorensen 2011 X       Median 34 (23‐44) for Down's cases; mean 30.4 (16‐45), 16.5% ≥ 35 for unaffected pregnancies Karyotyping or follow‐up to birth Routine screening Retrospective cohort Denmark
Spencer 1999 X   X X Median 38 (19‐46) for Down's cases, 36 (15‐47) for controls Invasive testing (high‐risk women) or follow‐up to birth Routine screening Case control UK
Spencer 2002         Median 36 (20‐44) for Down's cases, 30 (16‐41) for controls Not reported Routine screening Case control UK
Spencer 2008 X       Median 35.8 for Down's cases, 29.3 for controls Karyotyping or follow‐up to birth Routine screening Case control Denmark
Stenhouse 2004 X       Median 32 (14‐45), 27% ≥ 35 Invasive testing offered to women with screening risk of > 1:250 or follow‐up to birth Routine screening Prospective cohort UK
Strah 2008     X   Median 28.6 (15‐42) Karyotyping or follow‐up to birth Routine screening Cohort Slovenia
Theodoropoulos 1998     X   Median 29 (16‐48), 7.8% ≥ 37 CVS or amniocentesis or follow‐up to birth. Unclear reference standard in cases of intrauterine death, miscarriages and terminations. Routine screening Prospective cohort Greece
Thilaganathan 1999     X   Mean 29 (15‐45) CVS (offered to patients considered high risk on screening) or follow‐up to birth Routine screening Prospective cohort UK
Timmerman 2010         Mean 34.5 (19‐45) Karyotyping or follow‐up to birth Routine screening Prospective cohort Netherlands
Torring 2010 X       Mean 35 for Down's cases, 31 for controls Karyotyping or follow‐up to birth Routine screening Case control Denmark
Vadiveloo 2009 X       Median 33.1, 36.9% ≥ 35 Karyotyping or follow‐up to birth Routine screening Retrospective cohort UK
Valinen 2007 X       Mean 29.6, 18.6% ≥ 35 Karyotyping or follow‐up to birth Routine screening Retrospective cohort Finland
Viora 2003         Median 32 (18‐47) CVS or follow‐up to birth Routine screening Prospective cohort Italy
Wald 2003 X   X X Not reported Invasive testing (following second trimester screening) or follow‐up to birth Routine screening Case control UK and Austria
Wapner 2003* X   X   Mean 35 (SD 4.6), 50% ≥ 35 Invasive testing. Miscarriage with cytogenetic testing. Follow‐up to birth Routine screening Prospective cohort USA
Wax 2009 X       Mean 36.7 (SD 3.2) Karyotyping or follow‐up to birth Routine screening Retrospective cohort USA
Wojdemann 2005 X   X   Mean 29, 10.8% ≥ 35 Invasive testing (in cases of increased risk) or follow‐up to birth Referrals for screening Prospective cohort Denmark
Wortelboer 2009 X       Median 34.9 (15‐48) Karyotyping or follow‐up to birth Routine screening Cohort Netherlands
Wright 2008     X   Median 35.2 (16‐52) Karyotyping or follow‐up to birth Routine screening Cohort UK
Wright 2010 X       Median 31.9 (IQR 27.7‐35.8) Karyotyping or follow‐up to birth Routine screening Cohort UK, Denmark and Cyprus
Zoppi 2001     X   Median 33 (14‐48) Amniocentesis, CVS or follow‐up to birth Routine screening Prospective cohort Italy

*The study provided data for the subset of women with maternal age of 35 or more.

X indicates that the test was evaluated in the study.

CVS = chorionic villus sampling; IQR = interquartile range; SD = standard deviation.