Hildebrand 2010.

Study characteristics
Patient Sampling	Study design: retrospective observational study Recruitment: hospital records of pregnant women attending one of the participating hospitals for a second‐trimester anomaly scan during the study period were reviewed Study start and end date: September 2001 to August 2004
Patient characteristics and setting	Setting: multicentre (5) (4 secondary care facilities ‐ units from Norrköping, Motala, Jönköping and Värnamo; 1 tertiary care facility ‐ University Hospital in Linköping) Region(s) and country/countries from which participants were recruited: South‐eastern Sweden; Linköping, Norrköping, Motala, Jönköping and Värnamo Sample size: 14,024 Study eligibility criteria: pregnant women undergoing a second‐trimester anomaly scan with complete follow‐up data available. Infants/fetuses with minor anomalies were excluded from the analyses. Number of participants with the target condition: 264 Population type: unselected population Prior testing: none
Index tests	Type: single‐stage screening Second‐trimester scan: Timing: second trimester of pregnancy (Motala, Jönköping, Norrköping, Värnamo) Ultrasound scanning protocol: basic in 3 of the 4 participating centres offering a routine second‐trimester scan (Jönköping, Norrköping, Värnamo); in Motala, no standardised checklist for fetal anatomy was used Cardiac screening: basic in 3 of the 4 participating centres (Jönköping, Norrköping, Värnamo); in Linköping, no standardised checklist for the fetal heart was used Mode of examination: not reported Single or multiple operators: multiple Staff qualification and/or operator experience level: specially trained midwives, training consisted of 2 compulsory courses as well as practical training with an experienced midwife Notes: At the fifth unit (Linköping), the routine scan was performed at 11 to 14 weeks' gestation and no routine second‐trimester scan was offered. The 11‐ to 14‐week scan did not meet our inclusion criteria because the scan did not include a routine anatomical survey.
Target condition and reference standard(s)	Target condition(s): major fetal structural anomalies Definitions used for major and minor congenital abnormalities: fetal anomaly diagnoses were grouped according to their likely clinical consequences: major anomalies (lethal), anomalies associated with long‐term handicap, anomalies potentially amenable to intrauterine treatment and fetal conditions that required postnatal investigation and/or treatment (as proposed by Royal College of Obstetricians and Gynaecologists in 1997) Reference standard (live birth): pregnancy and neonatal outcomes from hospital records, all structural anomalies diagnosed or suspected were obtained from each department; the Swedish maternal personal identification number was used to match obstetric and neonatal data Reference standard (fetal or neonatal demise): if available, pathology or autopsy records Postnatal follow‐up duration: first week after birth
Flow and timing	Eligible patients: 23,935 Exclusions (study investigator): 450 excluded (fetuses/infants with minor anomalies), 2746 incomplete follow‐up (11.7%) Exclusions (review team): 6692 (no routine second trimester anomaly scan); from the cases who did receive a routine second trimester scan, a further 23 cases were excluded (1 soft marker for chromosomal abnormalities, 16 abnormal karyotype, 6 anomalies considered minor by the review team)
Comparative
Notes	Funding source: FORSS, the Southeast Region medical research council, financially supported the study
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?			Unclear
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)?	No
Were all patients included in the analysis?	No
Could the patient flow have introduced bias?		High risk