The LBW cohort
The follow-up in the LBW cohort is described in . Overall, 1855 children were seen at home at the 2-month visit and their median age was 65 days. It was possible to see the vaccination card for 1830 children (99%) and only these children were included in the analyses of the effect of DTP on survival ().
Study profile. BCG, Bacille Calmette-Guerin vaccine; DTP, diphtheria-tetanus-pertussis vaccine.
DTP vaccination status
There were 618 (34%) DTP unvaccinated children at 2 months of age, called the delayed DTP group in the present analysis. Among the 1212 DTP vaccinated children, the mean age of vaccination was 51 days for both sexes. The median interval between the date of BCG vaccination and DTP vaccination was 46 days (25–75 percentiles: 44–51 days) in the BCG at birth group, whereas it was 0 days (25–75 percentiles: 0–19 days) in the delayed BCG arm. In the delayed BCG arm, 38% (159/421) received BCG before DTP, 53% (225/421) BCG and DTP simultaneously and 9% (37/421) BCG after DTP. The delayed DTP group had significantly lower anthropometric indices (), suggesting that the healthiest children received DTP early.
Health indicators for DTP vaccinated and DTP unvaccinated children at the 2-month visit
Several variables differed between the groups (). Mothers of delayed DTP children were younger, had less schooling and more children were twins. There were fewer unvaccinated children in Bandim where children are actively called for vaccination. Normally all children are breastfed to at least 12 months of age. However, the non-governmental organisation responsible for preventing maternal HIV transmission recommended infected mothers not to breastfeed. The proportion of non-breastfeeding children was similar in the two groups, suggesting that the proportion of HIV infected mothers was the same. The differences in health and socio-economic indicators were similar for boys and girls (data not shown).
Background factors for DTP vaccinated and DTP unvaccinated children
Vaccinations between 2 and 6 months of age
The rate of DTP vaccination between the 2-month and 6-month visits was higher in the early DTP group (1040 vaccinations per 43 672 observation days) than in the delayed DTP group (379 vaccinations per 42 771 observation days), the age-adjusted incidence rate ratio (IRR) being 2.28 (95% CI 2.01 to 2.60). The pattern was similar for boys (IRR 2.42; 95% CI 2.01 to 2.91) and girls (IRR 2.18; 95% CI 1.85 to 2.58). Among DTP unvaccinated children seen at the 6-month visit, 69% (323/471) had received DTP, the median age being 99 days (25–75 quartiles: 78–133). Of the 16 initially DTP unvaccinated children (five girls, 11 boys) who died between 2 and 6 months, at least five (three girls, two boys) received DTP before they died.
By the 6-month visit, 50 children had died (2.7%) (). The effect of DTP () differed significantly for girls and boys (). The DRR for early versus delayed DTP vaccination was 2.45 (95% CI 0.93 to 6.45) for girls and 0.53 (95% CI 0.23 to 1.20) for boys (p=0.018, test of homogeneity), suggesting a negative effect for girls and a protective effect for boys. We conducted additional analyses controlling for the health and socio-economic indicators in and , including birth weight, study area, sex, twinning, birth order, breastfeeding status, MUAC, consultations, maternal MUAC, mother's age, ethnic group, mother's schooling, living with the father, randomisation to BCG and randomisation to vitamin A. In this analysis excluding 152 children and four deaths due to missing observations, the DRR for DTP vaccinated versus the delayed DTP group was 2.55 (95% CI 0.92 to 7.11) for girls and 0.36 (95% CI 0.14 to 0.89) for boys (p=0.004). DTP had similar effects among children who had received vitamin A at birth and those who had not.18
In the early DTP group, age at vaccination or time between DTP vaccination and the 2-month visit did not affect subsequent mortality (data not shown). Verbal autopsy did not suggest major differences in causes of death between sex or vaccine groups (see online supplementary appendix table).
DRR between 2 and 6 months of age according to initial vaccination status and sex
Figure 2 Accumulated mortality curves for DTP vaccinated and not yet DTPvaccinated children at 2 months of age for females and males. As 1% of the children had the 2-month visit after 3 months of age, the number at risk increased between 3 and 4 months of age. (more ...)
We adjusted for nutritional status to control for the healthy vaccinee effect (). In multiple Cox regression analyses, MUAC was the main determinant although all anthropometric indices were strongly associated with mortality if MUAC was not included. Adjusted for MUAC at the 2-month visit, the DRR for the early versus delayed DTP group was 2.62 (95% CI 1.34 to 5.09), being 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, test of homogeneity). With follow-up to 9 months of age, the DRR was 4.46 (95% CI 1.55 to 12.8) for girls and 1.28 (95% CI 0.61 to 2.68) for boys (p=0.043). Adjustment for weight-for-age z scores produced essentially similar results, the DRR being 5.37 (95% CI 1.71 to 16.9) for girls and 1.16 (95% CI 0.50 to 2.72) for boys (p=0.019). Adjusting for height-for-age z scores, the DRR was 3.26 (95% CI 1.17 to 9.07) for girls and 0.75 (95% CI 0.33 to 1.69) for boys (p=0.022).
The negative effect for girls was similar whether they had been DTP vaccinated shortly before the 2-month visit or earlier: the DRR was 5.79 (95% CI 1.39 to 24.2) for those vaccinated within 7 days and 6.25 (95% CI 1.87 to 20.0) for those vaccinated within 14 days of the 2-month visit.
The negative effect of DTP was stronger in the BCG arm (DRR 4.33; 95% CI 1.54 to 12.2) than in the delayed BCG arm (DRR 1.71; 95% CI 0.73 to 4.01) (p=0.147) (). The negative effect for girls was seen in both the BCG arm (DRR 7.18; 95% CI 1.53 to 33.7) and the delayed BCG arm (DRR 4.26; 95% CI 0.96 to 18.9).
Nutritional status of children who died
For boys, all nutritional indices at the 2-month visit were significantly associated with mortality between the 2-month and 6-month visits (). However, for girls, most of these indices were not significantly associated with mortality (). For all seven nutritional indices, the association was significantly different for boys and girls (tests of homogeneity). For boys the effect was similar in the early and delayed DTP groups; for girls the pattern could only be assessed for the early DTP group as there were too few deaths in the delayed DTP group.
Differences in nutritional status between children who died and those who survived according to sex