van Velzen 2016.

Study characteristics
Patient Sampling	Study design: retrospective observational study Recruitment: all cases with a prenatal or postnatal diagnosis of severe congenital heart defects within the studied region were identified using the prenatal ultrasound databases (prenatal cases) and the paediatric cardiology departmental databases and cross‐checked with catheterisation schedules, operating schedules and emergency admissions (postnatal cases) of the tertiary care centres servicing the region Study start and end date: 2007 to 2011
Patient characteristics and setting	Setting: multicentre; 3 tertiary care facilities (Academic Medical Centre Amsterdam, VU Medical Centre Amsterdam and Leiden University Medical Centre Leiden) responsible for the care of children with congenital heart defects in the studied region and all affiliated primary and secondary healthcare centres offering prenatal screening Region(s) and country/countries from which participants were recruited: north‐west region of the Netherlands Sample size: 720,079 Study eligibility criteria: cases with a pre‐ or postnatal diagnosis of a severe congenital heart defect irrespective of the presence or absence of additional congenital anomalies were included. For inclusion, the mother of the fetus or the infant had to be resident within the study region at the time of birth. Number of participants with the target condition: 992 Population type: unselected population Prior testing: not reported
Index tests	Type: single‐stage screening Second‐trimester scan: Timing (weeks and days gestation): 18 to 22 weeks’ gestation Ultrasound scanning protocol: detailed Cardiac screening: extended Mode of examination: not reported Single or multiple operators: multiple Staff qualification and/or operator experience level: certified according to Fetal Medicine foundation criteria
Target condition and reference standard(s)	Target condition(s): severe congenital heart defects Definitions used for major and minor congenital abnormalities: severe congenital heart defects were defined as being potentially life‐threatening and requiring surgery or intervention within the first year of life Reference standard (live birth): pregnancy and neonatal outcomes were obtained from hospital records. The case list was complemented with all postnatally diagnosed infants with a congenital heart defect who needed surgery or therapeutic cardiac catheterisation or who died within the first year of life. The postnatal echocardiography, surgical report or magnetic resonance imaging determined the definitive diagnosis in the analysis of the data. Reference standard (fetal or neonatal demise): the postmortem databases of the departments of pathology were studied for cardiac anomalies Postnatal follow‐up duration: first year of life
Flow and timing	Eligible patients: 720,138 Exclusions (study investigator): 53 excluded (date of birth in 2012 or postnatal cases with the first cardiac surgery after the age of 12 months), 6 lost to follow‐up (< 0.1% of total cohort, 0.4% of cases with eligible congenital heart defects) Exclusions (review team): no further exclusions
Comparative
Notes	Funding source: the authors declared that no financial support was obtained for this study
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?			Low concern
DOMAIN 2: Index Test (First‐trimester scan)
DOMAIN 2: Index Test (First + second‐trimester scan)
DOMAIN 2: Index Test (Single 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 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?	Yes
Could the patient flow have introduced bias?		High risk