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Research

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5170 (Published 13 October 2016) Cite this as: BMJ 2016;355:i5170
  1. Julian P T Higgins, professor of evidence synthesis1,
  2. Karla Soares-Weiser, deputy editor in chief2,
  3. José A López-López, research associate1,
  4. Artemisia Kakourou, research associate3,
  5. Katherine Chaplin, research associate1,
  6. Hannah Christensen, lecturer in infectious disease mathematical modelling1,
  7. Natasha K Martin, senior lecturer1 4,
  8. Jonathan A C Sterne, professor of medical statistics and epidemiology,1,
  9. Arthur L Reingold, professor and head of epidemiology5
  1. 1School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
  2. 2Cochrane, St Albans House, London SW1Y 4QX, UK
  3. 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  4. 4Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
  5. 5Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7358, USA
  1. Correspondence to: J Higgins julian.higgins{at}bristol.ac.uk
  • Accepted 16 September 2016

Abstract

Objectives 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.

Design Systematic review, including assessment of risk of bias, and meta-analyses of similar studies.

Study eligibility criteria 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.

Data sources 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.

Footnotes

  • We are indebted to Ana Maria Henao-Restrepo and Ximena Riveros de Laurie (Department of Immunization Vaccines and Biologicals, WHO) for their support throughout the project and to all members of the SAGE Working Group on non-specific effects of vaccines for their input. Nicola Low, Pippa Scott, and Matthias Egger wrote the initial draft of the protocol but did not contribute further to the review. We are grateful to Jelena Savović for help with designing data extraction forms. We thank Michelle Beam, Emi Han, Emma Smith, and Paul Zhang for screening of title and abstracts; Maria Christou for screening of full text articles; and Molly Grimes for copy editing. Contributions of NKM and HC are under the terms of postdoctoral research training fellowships issued by the UK National Institute for Health Research (NIHR); the views expressed in this publication are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health.

  • Contributors: ALR, KSW, and JPTH were invited to lead the review by WHO staff, on the basis of an existing draft protocol. ALR, KSW, and JPTH revised the protocol. KSW, AK, and ALR selected articles for inclusion. AK, KSW, and JLL extracted data. JLL and JPTH selected results for inclusion. JPTH, KC, HC, and NKM assessed risk of bias. JPTH and JLL did the analyses. JPTH, KSW, and ALR contributed substantially to interpretation of results. KSW and JPTH prepared tables and figures. JPTH wrote the first draft of the paper, and all authors revised it critically for important intellectual content. All authors have approved this version for publication. JPTH is the guarantor.

  • Funding: This work was funded in part by the World Health Organization. The work was commissioned as an independent evidence review by WHO. WHO staff provided advice about the topic area throughout the project, supported the search of bibliographic databases, and contributed to the identification of overlapping birth cohorts.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: grant support from WHO for undertaking the research; no other support from any organisation for the submitted work; no other financial relationships with any other organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not needed.

  • Transparency declaration: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/.

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