title: Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.
abstract: OBJECTIVE
  To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A.
  
  
  METHODS
  Systematic review, including assessment of risk of bias, and meta-analyses of similar studies.
  
  
  METHODS
  Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5.
  
  
  METHODS
  Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified.
  
  
  RESULTS
  Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV.
  
  
  CONCLUSIONS
  Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK julian.higgins@bristol.ac.uk.
authors.forename: Julian P T
authors.initials: JP
authors.lastname: Higgins
authors.affiliation: Cochrane, St Albans House, London SW1Y 4QX, UK.
authors.forename: Karla
authors.initials: K
authors.lastname: Soares-Weiser
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: José A
authors.initials: JA
authors.lastname: López-López
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
authors.forename: Artemisia
authors.initials: A
authors.lastname: Kakourou
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Chaplin
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Christensen
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Martin
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
authors.forename: Jonathan A C
authors.initials: JA
authors.lastname: Sterne
authors.affiliation: Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7358, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Reingold
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004165:Diphtheria / Q000401:mortality / Q000517:prevention & control; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage*; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D007223:Infant; D008297:Male; D008457:Measles / Q000401:mortality / Q000517:prevention & control; D008458:Measles Vaccine / Q000008:administration & dosage*; D009026:Mortality / Q000639:trends*; D013742:Tetanus / Q000401:mortality / Q000517:prevention & control; D014376:Tuberculosis / Q000401:mortality / Q000517:prevention & control; D006113:United Kingdom; D014611:Vaccination / Q000706:statistics & numerical data*; D014917:Whooping Cough / Q000401:mortality / Q000517:prevention & control
chemical_list: D001500:BCG Vaccine; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D008458:Measles Vaccine