Bister 2011.

Study characteristics
Patient Sampling	Study design: retrospective observational study Recruitment: pre‐ and postnatal hospital records from the obstetric ultrasound department, regional Craniofacial Unit and Perinatal Pathology department were reviewed to identify fetuses and neonates with pre‐ or postnatally diagnosed orofacial clefts Study start and end date: 1993 to 1997
Patient characteristics and setting	Setting: tertiary care facility (Addenbrooke’s Hospital), servicing the Cambridge area Region(s) and country/countries from which participants were recruited: Cambridge, United Kingdom Sample size: 23,573 Study eligibility criteria: ultrasound examination at 18 to 20 weeks of gestation Number of participants with the target condition: 26 Population type: unselected population Prior testing: dating scan
Index tests	Type: single‐stage screening Second‐trimester scan: Timing: 18 weeks to 20 weeks of gestation Ultrasound scanning protocol: not reported Cardiac screening: not applicable Mode of examination: not reported Single or multiple operators: multiple Staff qualification and/or operator experience level: trained sonographers, 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 outcomes from hospital records Reference standard (fetal or neonatal demise): review of autopsy records of fetuses over 16 weeks’ gestation Postnatal follow‐up duration: not reported
Flow and timing	Eligible patients: 23,577 Exclusions (study investigator): 4 excluded (1 considered not detectable by antenatal ultrasound, 1 no screening received until third trimester, 2 spontaneous fetal death) Exclusions (review team): none
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