Fleurke‐Rozema 2016.

Study characteristics
Patient Sampling	Study design: population‐based retrospective cohort study Recruitment: pre‐ and postnatally diagnosed cases of cleft lip with or without cleft palate were identified from the Perinatal Registry and Dutch Association for Cleft Palate and Craniofacial Anomalies register Study start and end date: January 2008 to December 2012
Patient characteristics and setting	Setting: geographical regions covered by 2 tertiary care facilities (Academic Medical Center and University Medical Center of Groningen) Region(s) and country/countries from which participants were recruited: north‐western and north‐eastern region of the Netherlands Sample size: 221,863 Study eligibility criteria: all isolated and non‐isolated cases with a pre‐ or postnatal diagnosis of cleft lip with or without cleft palate were included in the study Number of participants with the target condition: 227 Population type: unselected population Prior testing: not reported
Index tests	Type: single‐stage screening Second‐trimester scan: Timing (weeks and days gestation): 18 to 23 weeks’ 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: certified by the Dutch medical authorities
Target condition and reference standard(s)	Target condition(s): cleft lip with or without cleft palate Definitions used for major and minor congenital abnormalities: not reported Reference standard (live birth): pregnancy and neonatal outcomes from hospital records, data from paediatric surgeons' lists, the Dutch Association for Cleft Palate and Craniofacial Anomalies registry and The Netherlands Perinatal Registry Reference standard (fetal or neonatal demise): birth records from 16 weeks’ gestation were available in The Netherlands Perinatal Registry Postnatal follow‐up duration: not reported
Flow and timing	Eligible patients: 222,000 Exclusions (study investigator): none reported Exclusions (review team): 137 (103 cases with associated major anomalies, 34 cases who did not receive the index test)
Comparative
Notes	Funding source: this study was funded by the Netherlands Organization of Health Research and Development (ZonMw, project number 200320012)
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