Takita 2016.

Study characteristics
Patient Sampling	Study design: prospective observational study Recruitment: pregnant women attending the study centre for first‐ and second‐trimester prenatal screening Study start and end date: February 2011 to September 2013
Patient characteristics and setting	Setting: tertiary care facility (Showa University Hospital) Region(s) and country/countries from which participants were recruited: Shinagawa‐Ku, Tokyo, Japan Sample size: 2010 Study eligibility criteria: singleton pregnancy, delivery at the study centre. Patients referred for an ultrasound diagnosis of morphological abnormalities or other complications were excluded. Number of participants with the target condition: 35 Population type: unselected population Prior testing: not reported
Index tests	Type: two‐stage screening First‐trimester scan: Timing (weeks and days gestation): 11 to 13 weeks and 6 days of gestation Ultrasound scanning protocol: basic Cardiac screening: basic Mode of examination: transabdominal alone Single or multiple operators: multiple (6) Staff qualification and/or operator experience level: certified by the Fetal Medicine Foundation Second‐trimester scan: Timing (weeks and days gestation): 18 to 20 weeks and 6 days of gestation Ultrasound scanning protocol: detailed Cardiac screening: extended Mode of examination: transabdominal alone Single or multiple operators: multiple (6) Staff qualification and/or operator experience level: certified by the Fetal Medicine Foundation
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): after delivery, neonatal congenital abnormalities were reviewed and compared with the ultrasound findings obtained in the first and second trimesters Reference standard (fetal or neonatal demise): not reported Postnatal follow‐up duration: until neonatal examination
Flow and timing	Eligible patients: 2028 Exclusions (study investigator): none reported Exclusions (review team): 18 (6 soft markers for chromosomal abnormalities, 12 abnormal karyotype)
Comparative
Notes	Funding source: the authors declared that there are no financial or other relations that could lead to a conflict of interest. The funding source for this work was not specified.
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)
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)?	Unclear
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		Unclear risk