Is diphtheria-tetanus-pertussis (DTP) associated with increased female mortality? A meta-analysis testing the hypotheses of sex-differential non-specific effects of DTP vaccine

Trans R Soc Trop Med Hyg. 2016 Dec;110(10):570-581. doi: 10.1093/trstmh/trw073. Epub 2016 Nov 17.


Background: Ten years ago, we formulated two hypotheses about whole-cell diphtheria-tetanus-pertussis (DTP) vaccination: first, when given after BCG, DTP increases mortality in girls and, second, following DTP there is an increase in the female/male mortality rate ratio (MRR). A recent review by WHO found no convincing evidence that DTP increases mortality in females.

Methods: We used previous DTP reviews as well as the recent WHO review for assessing the hypotheses. As pre-specified we excluded studies with survival or frailty bias; if children had received BCG and DTP simultaneously; and if the children had received neonatal vitamin A.

Results: In seven studies of BCG-vaccinated children, DTP vaccination was associated with a 2.54 (95% CI 1.68-3.86) increase in mortality in girls (with no increase in boys [ratio 0.96, 0.55-1.68]). In 10 studies of BCG-vaccinated children, the female-to-male mortality ratio was 2.45 (1.48-4.06) times higher after DTP than before DTP. In 15 studies of children who had received DTP after previous BCG vaccination, mortality was 1.53 (1.21-1.93) times higher in girls than boys. The findings were similar in studies conducted before and after formulation of the hypotheses.

Conclusions: The two hypotheses were confirmed in the studies that fulfilled pre-specified criteria.

Keywords: BCG; DTP; Diphtheria-tetanus-pertussis vaccine; Non-specific effects of vaccines; Sex-differential effects; Strategic Advisory Group of Experts on Immunization (SAGE).

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Diphtheria-Tetanus-Pertussis Vaccine / administration & dosage
  • Diphtheria-Tetanus-Pertussis Vaccine / adverse effects*
  • Diphtheria-Tetanus-Pertussis Vaccine / immunology
  • Evidence-Based Medicine
  • Female
  • Humans
  • Infant
  • Male
  • Observational Studies as Topic
  • Randomized Controlled Trials as Topic
  • Sex Characteristics
  • Sex Factors
  • Survival Analysis
  • Vaccination / mortality*


  • Diphtheria-Tetanus-Pertussis Vaccine