Bodin 2018.

Study characteristics
Patient Sampling	Study design: population‐based retrospective cohort study based on data from the Danish Fetal Medicine Database (DFMD) Recruitment: data from all obstetric departments in Denmark are registered in the database Study start and end date: January 2008 to December 2015
Patient characteristics and setting	Setting: national fetal malformation registry Region(s) and country/countries from which participants were recruited: data included from all obstetric departments in Denmark Sample size: 443,465 Study eligibility criteria: all pregnancies that underwent a second‐trimester ultrasound scan and had a pre‐ or postnatally registered diagnosis of open spina bifida, meningocele or a lipomatous malformation with neurological deficit of a skin‐covered spina bifida, were included. Babies born and having had primary surgery outside of Denmark were excluded. All cases with spina bifida occulta, lipomatous malformations or tethered cord without neurological deficits, as well as suspected but not confirmed spina bifida cases, were excluded. Number of participants with the target condition: 234 Population type: unselected population Prior testing: 11 to 14 weeks ultrasound scan (scanning primarily for chromosomal abnormalities)
Index tests	Type: single‐stage screening Second‐trimester scan: Timing: 18 weeks to 21 weeks Ultrasound scanning protocol: not reported Cardiac screening: not reported Mode of examination: not reported Single or multiple operators: not reported Staff qualification and/or operator experience level: not reported
Target condition and reference standard(s)	Target condition(s): spina bifida, including meningocele and lipomatous malformations with neurological deficits of the skin‐covered spina bifida Definitions used for major and minor congenital abnormalities: European Registration of Congenital Anomalies and Twins (EUROCAT) classification system Reference standard (live birth): data were linked to postnatal outcomes from the Danish Cytogenetic Register, the National Patient Register and the National Birth Register Reference standard (fetal and neonatal demise): medical records on all infants and mothers in whom a termination of pregnancy was performed were evaluated Postnatal follow‐up duration: 1 year after birth
Flow and timing	Eligible patients: 475,679 Exclusions (study investigator): 32,203 excluded (32,062 no prenatal scan, 6 duplicates, 108 no spina bifida history, 23 spina bifida occulta or tethered cord, 4 other) Exclusions (review team): 11 (6 cases of spina bifida who had no prenatal scan, 5 cases of spina bifida with no information on prenatal screening)
Comparative
Notes	Funding source: this work received financial support from Region Midts Forskningsfond, Jascha Fonden, Fonden af 1870, NFOG
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