Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial

Abstract

BackgroundStudies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants.Methods2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit.ResultsTwo-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls.ConclusionSurprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.

Non-specific effects of vaccines: RCTs, not observational studies, are needed: Figure 1

“…In a recent paper by Aaby et al 21 have produced further data which attempt to control for nutritional status in an observational study, and confirm his previous findings on female infant mortality after DTP. While this concept may seem surprising, there are studies showing gender differences in innate immunity,22 adaptive immunity,23 autoimmunity24 and vaccine responses25 which provide some biological plausibility to the presence of differential effects of vaccines in relation to gender.…”

Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries

“…The survival curves in the studies comparing DTP-vaccinated and DTP-unvaccinated children also indicate that there is no clustering of early deaths in the DTP group 142 53 64 Consistent with the tendency of nurses and physicians not to vaccinate sick children, current data suggest that DTP vaccination is associated with a strong positive selection bias, with healthier and wealthier children coming first for vaccination 142 53 64 Due to ‘frailty bias’ among the DTP-unvaccinated children, DTP should be expected to be associated with a beneficial effect on child survival.…”

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

“…Apart from reporting bias, the only proposed biases working in the opposite direction have been that starting follow-up after vaccination (as would happen with data from demographic surveillance systems) could mean that frail children had already died in the unvaccinated group leading to higher measured mortality in the DTP group; secondly, censoring for MV during follow-up could mean that the healthiest DTP-children were measles vaccinated first and the frail were left to die in the DTP group. It has been shown specifically in one study that the delay in starting follow-up had no impact on the estimate 27 and several studies have started follow-up at the time of DTP vaccination 23,26 and found similar strong negative effects, so there is no evidence that this bias is important. Similarly, the studies which have tested whether censoring for MV matters have found no effect 8 and many studies have not censored for MV and still found a strong negative effect of DTP 2,6,23,25,40 so there is no evidence that this bias is important.…”

“…We included seven studies of children (who had previously received BCG) that compared the mortality rate of DTP-vaccinated and DTP-unvaccinated girls 2,6,24-27,40 (Table 1); the bias index varied between 0.5 and 1.7 in these studies. These studies had some form of age-adjustment.…”