Grande 2012.

Study characteristics
Patient Sampling	Study design: retrospective observational study Recruitment: hospital records of all pregnant women who received prenatal ultrasound screening between 11 and 14 weeks' gestation during the study period were reviewed Study start and end date: January 2002 to December 2009
Patient characteristics and setting	Setting: tertiary care facility (Department of Maternal‐Fetal Medicine, Hospital Clinic Barcelona) Region(s) and country/countries from which participants were recruited: Barcelona, Spain Sample size: 13,639 Study eligibility criteria: chromosomally normal singleton fetuses Number of participants with the target condition: 355 Population type: unselected population Prior testing: nuchal translucency measurement at the time of the first‐trimester scan in all pregnancies, combined test in pregnancies with increased risk for fetal trisomies
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: basic Mode of examination: transabdominal and transvaginal Single or multiple operators: multiple (19) Staff qualification and/or operator experience level: obstetricians (no further specification) Second‐trimester scan: Timing: 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): fetal structural anomalies (any type) Definitions used for major and minor congenital abnormalities: European Registration of Congenital Anomalies and Twins (EUROCAT) classification system Reference standard (live birth): hospital records on pregnancy outcome and neonatal follow‐up, or obstetricians or the women themselves were contacted by telephone Reference standard (fetal or neonatal demise): postmortem examination was systematically performed at fetal demise after 10 weeks’ gestation Postnatal follow‐up duration: until neonatal discharge
Flow and timing	Eligible patients: 16301 Exclusions (study investigator): excluded (312 abnormal karyotype, 103 single gene disorders, 230 fetal death before index test), 1933 lost to follow‐up (12.3%) Exclusions (review team): 84 (80 soft markers for chromosomal abnormalities, 4 non‐structural anomalies)
Comparative
Notes	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)
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?	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