Syngelaki 2011.

Study characteristics
Patient Sampling	Study design: retrospective observational study Recruitment: hospital records of pregnant women who received an 11‐ to 13‐week ultrasound scan at the participating centres were reviewed Study start and end date: March 2006 to September 2009
Patient characteristics and setting	Setting: multicentre (2) (Medway Maritime Hospital ‐ secondary care facility; King’s College Hospital ‐ tertiary care facility) Region(s) and country/countries from which participants were recruited: London and Gillingham, United Kingdom Sample size: 41,389 Study eligibility criteria: pregnant women with a viable singleton pregnancy, undergoing ultrasound screening at 11 to 13 weeks, excluding the cases with aneuploidies or no follow‐up Population type: unselected population Prior testing: nuchal translucency measurement at the time of the first‐trimester scan
Index tests	Type: two‐stage screening First‐trimester scan: Timing (weeks and days gestation): 11 weeks and 0 days to 13 weeks and 6 days of gestation Ultrasound scanning protocol: detailed Cardiac screening: basic Mode of examination: primary transabdominal, transvaginal if necessary Single or multiple operators: multiple (165) Staff qualification and/or operator experience level: (obstetric) sonographers certified by the Fetal Medicine Foundation Second‐trimester scan: Timing: 20 weeks and 0 days to 23 weeks and 6 days of gestation Ultrasound scanning protocol: detailed Cardiac screening: extended Mode of examination: transabdominal alone Single or multiple operators: multiple (165) Staff qualification and/or operator experience level: (obstetric) sonographers certified by the Fetal Medicine Foundation
Target condition and reference standard(s)	Target condition(s): fetal structural anomalies (any type) Definitions used for major and minor congenital abnormalities: not reported Reference standard (live birth): pregnancy outcome from hospital records, neonatal examination by a paediatrician Reference standard (fetal or neonatal demise): postmortem examination (not in all cases) Postnatal follow‐up duration: until neonatal discharge
Flow and timing	Eligible patients: 45,191 Exclusions (study investigator): 332 excluded (aneuploidy), 3466 lost to follow‐up (2739 no follow‐up, 116 pregnancy terminations after normal first trimester scan, 611 fetal death after normal index test results) (7.7%) Exclusions (review team): 4 (unilateral short long bone)
Comparative
Notes	Funding source: this study was supported by a grant from the Fetal Medicine Foundation (Charity No: 1037116)
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
Could the selection of patients have introduced bias?		Low risk
Are there concerns that the included patients and setting do not match the review question?			High
DOMAIN 2: Index Test (First‐trimester scan)
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
Could the conduct or interpretation of the index test have introduced bias?		Low risk
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 2: Index Test (First + second‐trimester scan)
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
Could the conduct or interpretation of the index test have introduced bias?		Low risk
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 2: Index Test (Single second‐trimester scan)
DOMAIN 3: Reference Standard
Is the reference standard likely to correctly classify anomalies that are externally visible, present with clinically relevant symptoms shortly after birth, or that are considered to be lethal/incompatible with life?	Yes
Is the reference standard likely to correctly classify anomalies that may present after discharge from postnatal care?	No
Were the reference standard results interpreted without knowledge of the results of the index test?	No
Could the reference standard, its conduct, or its interpretation have introduced bias?		High risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			Low concern
DOMAIN 4: Flow and Timing
Did all live‐born infants receive a reference standard?	Yes
Did all live‐born infants receive the same reference standard?	No
Did all cases of fetal or perinatal loss receive the reference standard (including termination of pregnancy, intra‐uterine death, stillbirth, perinatal mortality)?	No
Were all patients included in the analysis?	No
Could the patient flow have introduced bias?		High risk