Kenkhuis 2018.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: all pregnant women who chose to have a combined test during the study period were asked to participate in the study Study start and end date: November 2012 to December 2015
Patient characteristics and setting	Setting: multicentre (8) (6 ultrasound practices ‐ primary care facilities; Isala Hospital ‐ secondary care facility; University Medical Center Groningen ‐ tertiary care facility) Region(s) and country/countries from which participants were recruited: Groningen and Overrijsel, the Netherlands Sample size: 5021 Study eligibility criteria: high‐ and low‐risk pregnant women opting for the combined test Number of participants with the target condition: 68 Population type: pregnant women opting for the combined test Prior testing: combined test at the time of the first‐trimester scan
Index tests	Type: two‐stage screening First‐trimester scan: Timing (weeks and days gestation): 11 weeks and 0 days 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: sonographers, certified for the performance of nuchal translucency measurement Second‐trimester scan: Timing: in the 20th week of 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: not reported Reference standard (live birth): pregnancy and neonatal outcomes from hospital records, follow‐up forms provided to participating practices and hospitals Reference standard (fetal or neonatal demise): if available, pathology records Postnatal follow‐up duration: not reported
Flow and timing	Eligible patients: 5534 Exclusions (study investigator): 495 lost to follow‐up (8.9%) Exclusions (review team): 18 (1 soft marker for chromosomal abnormalities, 17 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?			Unclear
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?	Unclear
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?		Unclear 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?	No
Could the patient flow have introduced bias?		Unclear risk