Boyd 2000‐4.

Study characteristics
Patient Sampling	Study design: population‐based retrospective cohort study based on data from the European Registration of Congenital Anomalies and Twins (EUROCAT) database from 18 congenital malformation registers from 11 European countries Recruitment: all live births, still births and pregnancies that result in termination after a structural or chromosomal abnormality has been detected prenatally by ultrasound scan or diagnosed within 7 days of birth are registered in the database Study start and end date: duration ranging between 9 and 30 months, period not further specified
Patient characteristics and setting	Setting: congenital malformation registry Region(s) and country/countries from which participants were recruited: Mainz, Germany Sample size: 9535 Study eligibility criteria: congenital malformations from all live births, still birth and pregnancies that result in termination after a structural or chromosomal abnormality has been detected prenatally by ultrasound scan or diagnosed within 7 days of birth Number of participants with the target condition: 16 Population type: unselected population Prior testing: first‐trimester dating scan; alpha‐fetoprotein screening
Index tests	Type: single‐stage screening Second‐trimester scan: Timing: around 20 weeks’ gestation Ultrasound scanning protocol: not reported Cardiac screening: not reported Mode of examination: not reported Single or multiple operators: multiple (population‐based) Staff qualification and/or operator experience level: trained operators, not further specified
Target condition and reference standard(s)	Target condition(s): anencephaly, spina bifida Definitions used for major and minor congenital abnormalities: EUROCAT classification system Reference standard (live birth): multiple sources of ascertainment and active case finding, following the EUROCAT guidelines Reference standard (fetal or neonatal demise): pathology or autopsy records, following EUROCAT guidelines Postnatal follow‐up duration: 7 days after birth
Flow and timing	Eligible patients: 9535 (Mainz, Germany); 670,766 (total cohort) Exclusions (study investigator): none reported Exclusions (review team): no cases excluded from Mainz, Germany; 128,539 cases excluded from total cohort (no routine prenatal screening in registry area: 8788 from Odense, Denmark, 34,085 from Northern Netherlands; 47,895 from South Western Netherlands; registry not population‐based: 8745 from Leipzig, Germany; 29,026 from Styria, Austria)
Comparative
Notes	Funding source: the Euroscan Study has received support from the European Union Biomed 2 Concerted Action
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)?	Unclear
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		Unclear risk