Maarse 2011.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: all screened pregnant women in the geographic region were included Study start and end date: January 2007 to December 2008
Patient characteristics and setting	Setting: multicentre; 25 non‐profit ultrasound screening centres (primary/secondary care facilities) belonging to the Wilhelmina's Children's Hospital referral network (tertiary care facility) Region(s) and country/countries from which participants were recruited: Utrecht, the Netherlands Sample size: 35,924 Study eligibility criteria: pregnant women undergoing ultrasound screening in 25 centres, separated into a low‐risk and high‐risk population based on positive family history of orofacial clefts or other risk factors for fetal abnormalities Number of participants with the target condition: 54 Population type: low‐risk population Prior testing: not reported
Index tests	Type: single‐stage screening Second‐trimester scan: Timing: 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: trained midwives, sonographers and obstetricians, not further specified
Target condition and reference standard(s)	Target condition(s): orofacial clefts Definitions used for major and minor congenital abnormalities: not reported Reference standard (live birth): pregnancy and neonatal outcome were obtained from medical records Reference standard (fetal or neonatal demise): autopsy was recommended to verify the prenatal diagnosis, no further specification on uptake of autopsy following fetal demise Postnatal follow‐up duration: not reported
Flow and timing	Eligible patients: 38,760 Exclusions (study investigator): none reported Exclusions (review team): 2836 (high‐risk pregnant women)
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?			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