Iliescu 2013.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: an extended first‐trimester ultrasound scan was performed in 5472 consecutive women attending the participating study centres Study start and end date: January 2010 to March 2012
Patient characteristics and setting	Setting: multicentre (2) (University of Craiova ‐ tertiary care facility; University of Athens ‐ tertiary care facility) Region(s) and country/countries from which participants were recruited: Craiova, Romania; Athens, Greece Sample size: 4791 Study eligibility criteria: written informed consent before ultrasound examination Number of participants with the target condition: 129 Population type: unselected population Prior testing: nuchal translucency measurement
Index tests	Type: two‐stage screening (data were only included for the first‐trimester scan): First‐trimester scan: Timing (weeks and days gestation): 12 gestational weeks to 13 weeks and 6 days of gestation Ultrasound scanning protocol: detailed Cardiac screening: extended Mode of examination: primary transabdominal, transvaginal if necessary Single or multiple operators: multiple Staff qualification and/or operator experience level: trained and certified obstetricians with more than 5 years of experience Second‐trimester scan: Data for the second‐trimester scan were excluded on index test timing (16 to 26 weeks' gestation)
Target condition and reference standard(s)	Target condition(s): structural anomalies Definitions used for major and minor congenital abnormalities: major was defined as lethal anomalies or anomalies with severe immediate or long‐term morbidity. Moderate or minor was defined as anomalies with short‐ or long‐term morbidity of minor or moderate severity. Reference standard (live birth): neonatal examination by a paediatrician Reference standard (fetal or neonatal demise): following termination of pregnancy or intrauterine demise the case was examined by an interdisciplinary team of pathologists and obstetricians Postnatal follow‐up duration: 3 days after birth
Flow and timing	Eligible patients: 5021 Exclusions (study investigator): 645 lost to follow‐up (11.8%) Exclusions (review team): 36 (9 soft markers for chromosomal abnormalities, 17 abnormal karyotype, 2 anomalies considered not detectable by prenatal ultrasound, 5 non‐structural anomalies, 1 normal variant, 1 anomalies secondary to intra‐uterine infection, 1 abnormal biometric measurements)
Comparative
Notes	First‐trimester false‐positive diagnoses are reported overall, but not per anomaly. As these data may include false‐positive diagnoses for soft markers for chromosomal abnormalities, we have decided not to extract the overall numbers of false‐positive diagnoses for the meta‐analysis. Funding source: not reported
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)?	Yes
Were all patients included in the analysis?	No
Could the patient flow have introduced bias?		Unclear risk