Petousis 2020.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: all pregnant women attending the study centre for a routine first trimester scan during the study period were eligible for inclusion in the study Study start and end date: June 2013 to May 2017
Patient characteristics and setting	Setting: tertiary care facility (Aristotle University of Thessaloniki) Region(s) and country/countries from which participants were recruited: Thessaloniki, Greece Sample size: 3263 Study eligibility criteria: pregnant women with a singleton pregnancy who attended the study centre for a first‐trimester ultrasound between 11 and 14 weeks, a second trimester scan between 20 and 24 weeks and a known pregnancy outcome, were included in the study. Only cases with a confirmed or apparently normal karyotype were included in the analysis. Number of participants with the target condition: 57 Population type: unselected population Prior testing: nuchal translucency measurement at the time of the first‐trimester scan
Index tests	Type: two‐stage screening (data were only reported for the first‐trimester scan): 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 Staff qualification and/or operator experience level: certified by the Fetal Medicine Foundation Second‐trimester scan: Data to construct 2 x 2 tables could not be extracted or derived from the report
Target condition and reference standard(s)	Target condition(s): major fetal structural anomalies Definitions used for major and minor congenital abnormalities: European Registration of Congenital Anomalies and Twins (EUROCAT) classification system Reference standard (live birth): neonatal examination by a paediatrician Reference standard (fetal or neonatal demise): postmortem examination if available Postnatal follow‐up duration: until neonatal examination
Flow and timing	Eligible patients: 3378 Exclusions (study investigator): 17 excluded (abnormal karyotype), 98 lost to follow‐up or miscarried after normal index test (29%) Exclusions (review team): none excluded
Comparative
Notes	Funding source: no potential conflict of interest was reported by the authors. The funding source for this work was not specified.
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)
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?	Yes
Could the patient flow have introduced bias?		High risk