title: Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis.
abstract: BACKGROUND
  Birth defects remain a significant source of worldwide morbidity and mortality. Strong scientific evidence shows that folic acid fortification of a region's food supply leads to a decrease in spina bifida (a birth defect of the spine). Still, many countries around the world have yet to approve mandatory fortification through government legislation.
  
  
  OBJECTIVE
  We sought to perform a systematic review and meta-analysis of period prevalence of spina bifida by folic acid fortification status, geographic region, and study population.
  
  
  METHODS
  An expert research librarian used terms related to neural tube defects and epidemiology from primary research from 1985 to 2010 to search in EMBASE and MEDLINE. We searched the reference lists of included articles and key review articles identified by experts.
  
  
  METHODS
  Inclusion criteria included studies in English or French reporting on prevalence published between January 1985 and December 2010 that (1) were primary research, (2) were population-based, and (3) reported a point or period prevalence estimate of spina bifida (i.e., prevalence estimate with confidence intervals or case numerator and population denominator). Two independent reviewers screened titles and abstracts for eligible articles, then 2 authors screened full texts in duplicate for final inclusion. Disagreements were resolved through consensus or a third party.
  
  
  METHODS
  We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses, or PRISMA, abstracting data related to case ascertainment, study population, folic acid fortification status, geographic region, and prevalence estimate independently and in duplicate. We extracted overall data and any subgroups reported by age, gender, time period, or type of spina bifida. We classified each period prevalence estimate as "mandatory" or "voluntary" folic acid fortification according to each country's folic acid fortification status at the time data were collected (as determined by a well-recognized fortification monitoring body, Food Fortification Initiative). We determined study quality on the basis of sample representativeness, standardization of data collection and birth defect assessment, and statistical analyses. We analyzed study-level period prevalence estimates by using a random effects model (α level of < 0.05) for all meta-analyses. We stratified pooled period prevalence estimates by birth population, fortification status, and continent.
  
  
  RESULTS
  Of 4078 studies identified, we included 179 studies in the systematic review and 123 in a meta-analysis. In studies of live births (LBs) alone, period prevalences of spina bifida were (1) lower in geographical regions with mandatory (33.86 per 100,000 LBs) versus voluntary (48.35 per 100,000 LBs) folic acid fortification, and (2) lower in studies of LBs, stillbirths, and terminations of pregnancy in regions with mandatory (35.22 per 100,000 LBs) versus voluntary (52.29 per 100,000 LBs) fortification. In LBs, stillbirths, and terminations of pregnancy studies, the lowest pooled prevalence estimate was in North America (38.70 per 100,000). Case ascertainment, surveillance methods, and reporting varied across these population-based studies.
  
  
  CONCLUSIONS
  Mandatory legislation enforcing folic acid fortification of the food supply lags behind the evidence, particularly in Asian and European countries. This extensive literature review shows that spina bifida is significantly more common in world regions without government legislation regulating full-coverage folic acid fortification of the food supply (i.e., Asia, Europe) and that mandatory folic acid fortification resulted in a lower prevalence of spina bifida regardless of the type of birth cohort. African data were scarce, but needed, as many African nations are beginning to adopt folic acid legislation.
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Callie A M
authors.initials: CA
authors.lastname: Atta
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Fiest
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Frolkis
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jette
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pringsheim
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Christine
authors.initials: C
authors.lastname: St Germaine-Smith
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Thilinie
authors.initials: T
authors.lastname: Rajapakse
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Gilaad G
authors.initials: GG
authors.lastname: Kaplan
authors.affiliation: Callie A. M. Atta, Kirsten M. Fiest, Nathalie Jette, Tamara Pringsheim, and Christine St Germaine-Smith are with the Department of Clinical Neurosciences, University of Calgary, Alberta. Kirsten M. Fiest and Nathalie Jette are also with Hotchkiss Brain Institute, University of Calgary. Tamara Pringsheim and Thilinie Rajapakse are with the Department of Paediatrics, University of Calgary. Kirsten M. Fiest, Alexandra D. Frolkis, Nathalie Jette, Tamara Pringsheim, and Gilaad G. Kaplan are with Department of Community Health Sciences, University of Calgary. Amy Metcalfe is with the Department of Obstetrics and Gynecology, University of Calgary.
authors.forename: Amy
authors.initials: A
authors.lastname: Metcalfe
mesh_terms: D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000502:physiology; D005527:Food, Fortified / Q000592:standards*; D014943:Global Health / Q000331:legislation & jurisprudence / Q000706:statistics & numerical data*; D006801:Humans; D011247:Pregnancy; D015995:Prevalence; D016135:Spinal Dysraphism / Q000453:epidemiology* / Q000517:prevention & control; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000502:physiology
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid