title: Diphtheria-tetanus-pertussis vaccine administered simultaneously with measles vaccine is associated with increased morbidity and poor growth in girls. A randomised trial from Guinea-Bissau.
abstract: BACKGROUND
  Combined vaccination with diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) has been associated with increased mortality in observational studies. Among children missing MV and a dose of DTP and oral polio vaccine (OPV), we conducted a randomised trial of providing MV+DTP+OPV simultaneously, as currently recommended, or MV+OPV only, and examined the effect on morbidity and growth. We hypothesised that the MV+OPV group would experience less morbidity and grow better. Due to previous observations of sex differences in the non-specific effects of vaccinations, we analysed all data stratified by sex.
  
  
  METHODS
  At the Bandim Health Project in Guinea-Bissau, 568 children who were due to receive MV and who were missing either DTP3 or DTP booster were enrolled in the study. A subgroup of 332 children was followed intensively to register adverse events and infections in the first month after vaccination. A subgroup of 276 children was followed every third month for a year to monitor growth. All children were followed for one year for infectious diseases, consultations, and hospitalisations.
  
  
  RESULTS
  As expected, adverse events were more common in the MV+DTP+OPV group; diarrhoea and use of medication were increased among girls but not among boys (both p=0.02, test of interaction between DTP and sex). Febrile disease with vesicular rash, as well as consultations and hospitalisations tended to be more common in the MV+DTP+OPV group than in the MV+OPV group; the hazard ratio (HR) for febrile disease with vesicular rash was 1.86 (1.00; 3.47). The strongest tendencies for more febrile diseases and hospitalisations in the MV+DTP+OPV group were found in girls. Overall, growth did not differ by randomisation group. However, results differed by sex. Girls in the MV+DTP+OPV group had a consistent pattern of worse z-scores for weight, height, and mid-upper-arm-circumference (MUAC) than girls in the MV+OPV group. The effect was opposite for boys, with boys in the MV+OPV group faring worse than those in the MV+DTP+OPV group, the interaction test for sex and DTP being significant for weight at 6 and 9 months, for MUAC at 12 months and for weight-for-height at 3 and 9 months after randomisation.
  
  
  CONCLUSIONS
  This is the first randomised trial of the non-specific effects of DTP and supports that these effects may be sex-differential and of clinical and anthropometric importance. Combined vaccination with DTP+MV+OPV may be detrimental for girls.
authors.affiliation: Bandim Health Project, Indepth Network, Apartado 861, 1004 Bissau Codex, Guinea-Bissau. heja@dadlnet.dk
authors.forename: J
authors.initials: J
authors.lastname: Agergaard
authors.forename: E
authors.initials: E
authors.lastname: Nante
authors.forename: G
authors.initials: G
authors.lastname: Poulstrup
authors.forename: J
authors.initials: J
authors.lastname: Nielsen
authors.forename: K L
authors.initials: KL
authors.lastname: Flanagan
authors.forename: L
authors.initials: L
authors.lastname: Østergaard
authors.forename: C S
authors.initials: CS
authors.lastname: Benn
authors.forename: P
authors.initials: P
authors.lastname: Aaby
mesh_terms: D000886:Anthropometry; D002675:Child, Preschool; D003141:Communicable Diseases / Q000453:epidemiology*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D006130:Growth Disorders / Q000139:chemically induced*; D006169:Guinea-Bissau / Q000453:epidemiology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007223:Infant; D008297:Male; D008458:Measles Vaccine / Q000008:administration & dosage* / Q000009:adverse effects*; D011055:Poliovirus Vaccine, Oral / Q000008:administration & dosage; D012737:Sex Factors
chemical_list: D015721:Diphtheria-Tetanus-Pertussis Vaccine; D008458:Measles Vaccine; D011055:Poliovirus Vaccine, Oral