Orlandi 2014.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: unselected pregnant women referred to the study centre during the study period for first‐trimester screening of aneuploidies were eligible for inclusion Study start and end date: January 2009 to December 2011
Patient characteristics and setting	Setting: tertiary care facility (Centre for Prenatal Diagnosis of Palermo) Region(s) and country/countries from which participants were recruited: Palermo, Italy Sample size: 4021 Study eligibility criteria: pregnant women with a singleton pregnancy and crown‐rump length of 38 to 84 mm were included in the study. Cases lost to second‐trimester follow‐up or at delivery were excluded. Additionally, cases were excluded if cardiac morphology could not be visualised appropriately, both with a transabdominal and transvaginal approach. Number of participants with the target condition: 23 Population type: unselected population Prior testing: genetic screening at the time of the first‐trimester scan based on maternal age, levels of maternal serum free beta human chorionic gonadotrophin (hCG) and pregnancy‐associated plasma protein A (PAPP‐A), nuchal translucency measurement and presence of fetal nasal bone
Index tests	Type: two‐stage screening First‐trimester scan: Timing (weeks and days gestation): 11 to 14 weeks’ gestation Ultrasound scanning protocol: detailed Cardiac screening: extended Mode of examination: primary transabdominal, transvaginal if necessary Single or multiple operators: multiple (3) Staff qualification and/or operator experience level: certified by the Fetal Medicine Foundation Second‐trimester scan: Timing (weeks and days gestation): 20 to 22 weeks’ gestation Ultrasound scanning protocol: not reported Cardiac screening: not reported Mode of examination: not reported Single or multiple operators: not reported Staff qualification and/or operator experience level: not reported
Target condition and reference standard(s)	Target condition(s): cardiac anomalies (any type) Definitions used for major and minor congenital abnormalities: major was defined as the anomaly being either lethal or required surgery or interventional cardiac catheterisation during the first year of life in the newborn. Minor was defined as anomalies that are generally asymptomatic. Reference standard (live birth): neonatal examination by a neonatologist. Additional information provided by the mothers, or their gynaecologists. In cases where the infant underwent surgery, pertinent information was provided by the paediatric surgeon. Reference standard (fetal or neonatal demise): post‐mortem examination in cases in which the patients decided for termination of pregnancy was not available Postnatal follow‐up duration: follow‐up at 6 and 12 months
Flow and timing	Eligible patients: 4820 Exclusions (study investigator): 141 excluded (failure to visualise cardiac morphology properly at the first trimester scan), 649 lost to follow‐up (13.9%) Exclusions (review team): 9 (abnormal karyotype)
Comparative
Notes	False‐positive diagnoses were only reported for major cardiac anomalies; there were no false‐positive diagnoses among major cardiac anomalies Funding source: the authors declared that no funding was received for this work
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?	No
Could the selection of patients have introduced bias?		High 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?	Yes
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?		Low 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