BMJ  2004;329:1309 (4 December), doi:10.1136/bmj.38261.496366.82 (published 18 November 2004)

Paper

Non-specific effects of vaccination on child survival: prospective cohort study in Burkina Faso

¹ Institut de Recherche pour le Développement, Laboratoire Population, Environnement et Développement, BP 64501, 34394 Montpellier Cedex 5, France, ² Biostatem, Parc Scientifique G Besse, F 30035 Nîmes, France, ³ Unité d'Etudes et de Recherche en Démographie, 03 BP 7118, Ouagadougou 03, Burkina Faso

Abstract

Objective To study the effect of vaccination on mortality before 2 years of age in a developing country.

Design Prospective cohort study.

Setting Rural communities in Burkina Faso.

Participants 9085 children born in the study area between 1985 and 1993.

Main outcome measure Child death rate.

Results Mortality before 2 years of age was lower in the group of children who had been vaccinated: those vaccinated with BCG only had significantly lower mortality (0.37, 95% confidence interval 0.29 to 0.48) as did those vaccinated with diphtheria, tetanus, and pertussis only (0.24, 0.13 to 0.43). The second dose of diphtheria, tetanus, and pertussis was not associated with lower mortality (0.80, 0.58 to 1.12).

Conclusion Vaccination with diphtheria, tetanus, and pertussis as well as BCG is associated with better survival of children up to 2 years of age.

Introduction

Vaccination of children, particularly with measles vaccine, has been associated with reduced child mortality.^1-4 In Guinea-Bissau, recipients of one dose of diphtheria, tetanus, and pertussis vaccine had a higher mortality than those who received none of the childhood vaccines.⁵ We examined the association between vaccination and child mortality in Burkina Faso.

Materials and methods

We carried out a prospective survey of families living in 26 villages in Burkina Faso (Yako and Pissila area). Researchers visited the families every six months, although the average interval in 1993-5 was 12 months. We included all births up to 1993. At each visit the researchers recorded by month for the whole population, births, marriages, migrations, and deaths.⁶ The mean age of the children was 3.7 months at the first visit, 11.7 months at the second visit, and 20.0 months at the third visit. Data were collected on morbidity and use of health services. The arm circumference of each child was measured as an index of nutritional status.

The health system consisted of eight dispensaries in Yako only. The dispensaries usually had a few drugs, but people often used self medication (traditional or modern), consulted traditional healers, or relied on people who sold modern drugs. Some of the midwives were trained in modern modes of delivery.

Vaccination
Vaccination schedules followed World Health Organization recommendations. A card was given to the parents at the first vaccination. The researcher collected information from these cards at each visit. When the card was not seen, we assumed that the child had not been vaccinated. When a child died, the mother usually discarded its belongings, including vaccination cards. Similar traditions were observed in Guinea-Bissau.⁷

Statistical analysis
We used Kaplan-Meier plots and Cox proportional hazards models to analyse the association between vaccination and mortality. For adjusted analyses, we included all variables associated with mortality and vaccinations (5% level of significance).

For our first analysis, we introduced vaccination status as a time dependent covariate: we considered vaccinated children to be unvaccinated until the age of vaccination.⁸ Follow up was censored at the earliest event among 24 months, death, or out migration. We also censored at measles vaccination, if carried out, to exclude possible beneficial effects on survival.^1-3

To avoid bias from unregistered vaccinations, especially when death followed the vaccination and both events occurred between the same two visits, we replicated the method of the Guinea-Bissau study.⁵ Follow up began from the first visit (before seven months) and ended at the earliest among second visit, age 6 months after first visit, out migration, or death.

Results

During 1985-96, 9412 births were registered in the Pissila and Yako regions of Burkina Faso. We excluded 204 stillbirths and 123 infants with no recorded month of birth, leaving 9085 infants.

The death rate of these children was high: 90 per thousand in the first year, and 70 per thousand in the second year. By five years, the cumulative rate was 220 per thousand.

Most of the vaccinated children received either BCG (mean age 4.8 months for BCG before 24 months) followed by diphtheria, tetanus, and pertussis (mean age 6.3 months), or the vaccines simultaneously. Some children were vaccinated with BCG only, more rarely with diphtheria, tetanus, and pertussis only. Before 6 months of age, 45% (4049 of 9085) of the children received BCG or diphtheria, tetanus, and pertussis; 66% (5990 of 9085) were vaccinated before 24 months. Overall, 19% (583 of 3050) of the children aged 6 months and 70% (3892 of 5584) of those aged 24 months who had had one dose of diphtheria, tetanus, and pertussis, received a second dose (mean age 12.8 months); 39% (1531 of 3892) of them received measles vaccine simultaneously. Measles vaccine (mean age 12.7 months) was usually given with yellow fever vaccine.

All significant associations between mortality or vaccination and covariates were as expected—for example, the presence of a dispensary in the village was associated with reduced mortality and increased the likelihood of vaccination (see bmj.com).

Vaccination and mortality
Survival of vaccinated children from six to 24 months was significantly different to survival of unvaccinated children (figure).

View larger version (32K): [in this window] [in a new window]   Kaplan-Meier survival curves of children by vaccination status at 6 months of age

 

Vaccination with BCG was associated with lower mortality when data were analysed by vaccination status (risk ratio 0.37) and vaccination status recorded at the first visit (risk ratio 0.46). Risk ratios for diphtheria, tetanus, and pertussis were similar to BCG (table 1). Adjusted relative risks were also similar (table 1). Results for boys and girls were similar to those for the sexes combined (see bmj.com). The second dose of diphtheria, tetanus, and pertussis was not associated with lower mortality (table 2).

View this table: [in this window] [in a new window]   Table 1 Non-adjusted and adjusted risk ratios (95% confidence intervals) for mortality for BCG and diphtheria, tetanus, and pertussis vaccines analysed by vaccination status before age 2 years and vaccination status at first visit

 

View this table: [in this window] [in a new window]   Table 2 Risk ratios (95% confidence intervals) for mortality for second dose of diphtheria, tetanus, and pertussis vaccine among children vaccinated with BCG

 

Discussion

Vaccination of children in Burkina Faso with BCG and diphtheria, tetanus, and pertussis was associated with improved survival before 24 months. These effects remained unchanged when analyses were controlled for potential confounders, and were similar for both sexes.

Strengths and weaknesses of the study
The strengths of our study were, firstly, that the vaccination programme was independent of the survey, secondly, that the results were robust, and thirdly, that we studied a relatively large sample, including subgroups of vaccinated and unvaccinated children. Additionally, we found that the associations between covariates and survival, or vaccination, were as expected (see bmj.com).

Our study had three main weaknesses. Firstly, it was not a controlled trial, for ethical reasons. Although the results did not change when we considered a wide variety of covariates, including the use of the health service, nutritional status, and demographic variables, we cannot exclude the possibility that the results were influenced by unmeasured confounding effects. Secondly, there was a possibility of misclassification of vaccination status, particularly for dead children whose vaccination cards had been destroyed. To correct for this, we repeated all analyses by vaccination status recorded at the first visit. Thirdly, vaccines were not given independently. It has been stressed that vaccines were not distributed at random anywhere,⁹ and this was true of our study. Thus, most vaccinated children received all vaccines whereas others received none. Receipt of BCG and diphtheria, tetanus, and pertussis in particular were strongly correlated: about two thirds of the children vaccinated with BCG before 6 months of age also received diphtheria, tetanus, and pertussis.

Comparison with other studies
Our findings did not concur with those of a previous study, which found that early vaccination with diphtheria, tetanus, and pertussis impairs survival. Both studies were undertaken in areas of high mortality, and both had similar problems with misclassification of vaccination status.

Hypotheses have been formulated concerning the relation between mortality and sex.¹⁰ After adjustment for sex the results were similar to those with no adjustment for sex. All analyses carried out separately on boys and girls gave results similar to those for the sexes combined.

To maximise comparability between the two studies, we used similar methods for analysis. We had a group of 175 (19 in Guinea-Bissau) children who received diphtheria, tetanus, and pertussis but not BCG before the first visit and 433 children who were vaccinated first with diphtheria, tetanus, and pertussis. Our results were robust to the different methods of analysis.

The differences could be related to an earlier age at vaccination in Guinea-Bissau or to differences between the two regions. In Guinea-Bissau, deaths peaked at the end of the rainy season, whereas in Burkina Faso they peaked during the dry, hot season.¹¹ The causes of death and the efficacy of the vaccines should therefore be different. In Senegal, where mortality peaks at the end of the rainy season, diphtheria, tetanus, and pertussis vaccine was not associated with mortality.¹²

Issues for further research
The reduction in mortality associated with vaccination was greater than mortality from specific disease. The reasons for these unspecific effects remain unclear. Studies are needed to confirm whether higher survival is a consequence of vaccination or due to confounding effects.

What is already known on this topic In developing countries, vaccination with BCG is associated with better survival of children A study in Guinea-Bissau suggested that diphtheria, tetanus, and pertussis vaccine might be associated with lower survival What this study adds BCG and diphtheria, tetanus, and pertussis vaccines had no adverse effects on mortality in children A first dose of diphtheria, tetanus, and pertussis was associated with better survival

---

This is the abridged version of an article that was posted on bmj.com on 18 November 2004: http://bmj.com/cgi/doi/10.1136/bmj.38261.496366.82

Contributors: See bmj.com

Funding: This study was funded by a field research grant from Unicef and Eau, agriculture, et santé en milieu tropical, and an analysis grant from WHO.

Competing interests: SP has been a consultant statistician for Aventis Pasteur and Aventis Pasteur MSD on pertussis, rotavirus, and herpes zoster. EE has been funded by Aventis to attend a meeting.

Ethical approval: No ethical committee existed in Burkina Faso at the time of the demographic survey and at the start of this analysis of the database. Nevertheless, this study was approved by the Ministry of Health of Burkina Faso.

References

1. Hull HF, Williams PJ, Oldfield F. Measles mortality and vaccine efficacity in rural west Africa. Lancet Apr 30, 1983(8331): 972-5.
2. Koenig MA, Khan MA, Wojtyniak B, Clemens JD, Chakraborty J, Fauveau V. The impact of measles vaccination upon childhood mortality in Matlab, Bandgladesh. Bull WHO 1990;68: 441-7.[Web of Science][Medline]
3. Garenne M, Leroy O, Beau JP, Sene I. Efficacity of measles vaccines after controlling for exposure. Am J Epidmiol 1991;338: 183-94.
4. Vaugelade J. Demographic evaluation of a child health program in Burkina Faso in demographic evaluation of health programmes. Paris: Committee for International Co-operation in National Research in Demography, 1997: 123-30.
5. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321: 1435-9.[Abstract/Free Full Text]
6. Vaugelade J, Poirier J, Guiella G, Ouedrago R. Problématique et méthodologie des observatoires démographiques dans trois zones du Burkina Faso: Pissila, Niangoloko et Yako-Gourcy (1986-1996). Ouagadougou, Burkina Faso: IRD-UERD, 2000.
7. Jensen H. Analysis of multivariate survival data from longitudinal epidemiological studies: with special reference to the impact of routine immunisation in infancy. PhD Thesis. Denmark: University of Copenhagen, 2002.
8. Cox. Regression models and life-tables. J Roy Stat Soc Series B, 1972: 187-202.
9. Fine P. Commentary: an unexpected finding that needs confirmation or rejection. BMJ 2000;321: 1440.[Abstract/Free Full Text]
10. Aaby P, Jensen H, Samb B, Cisse B, Sodeman M, Jakobsen M, et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactived poliovirus: reanalysis of the West Afican studies. Lancet 2003;361: 2183-8.[CrossRef][Web of Science][Medline]
11. Vaugelade J. Variations de la mortalité saisonnière avant 5 ans selon le biotope en Afrique intertropicale. African population conference, Dakar, Senegal, International Union for the Scientific Study of the Population. Liège, Belgium: IUSSP, 1988: 3.4.51-61.
12. Aaby P, Samb B, Simondon F, Seck AM, Knudsen K, Whittle H. Non-specific beneficial effects of measles immunization: analysis of mortality studies from developing countries. BMJ 1995;311: 481-5.[Abstract/Free Full Text]

(Accepted 25 September 2004)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

This article has been cited by other articles:

• Chan, G. J, Moulton, L. H, Becker, S., Munoz, A., Black, R. E (2009). Author's Response. Int J Epidemiol 38: 323-324 [Full text]  
• Chan, G. J, Moulton, L. H, Becker, S., Munoz, A., Black, R. E (2007). Non-specific effects of diphtheria tetanus pertussis vaccination on child mortality in Cebu, The Philippines. Int J Epidemiol 36: 1022-1029 [Abstract] [Full text]  
• Saracci, R. (2007). Survival-related biases survive well. Int J Epidemiol 36: 244-246 [Full text]  
• Hviid, A., Wohlfahrt, J., Stellfeld, M., Melbye, M. (2005). Childhood Vaccination and Nontargeted Infectious Disease Hospitalization. JAMA 294: 699-705 [Abstract] [Full text]  
• Fine, P. E M (2005). Non-specific effects of vaccination: Author's reply to Shann. BMJ 330: 844-844 [Full text]  
• Aaby, P., Jensen, H., Benn, C. S., Lisse, I. M. (2005). Non-specific effects of vaccination: Survival bias may explain findings. BMJ 330: 844-845 [Full text]  
• Jensen, H., Benn, C. S, Aaby, P. (2005). DTP in low income countries: improved child survival or survival bias?. BMJ 330: 845-846 [Full text]  
• Fine, P. E M (2004). Non-specific "non-effects" of vaccination. BMJ 329: 1297-1298 [Full text]  

Rapid Responses:

Read all Rapid Responses

Replicating findings from Guinea-Bissau?

Peter Aaby, et al.
bmj.com, 25 Nov 2004 [Full text]

Non-specific beneficial effects of vaccinations in Burkina Faso: Survival bias?

Henrik Jensen, et al.
bmj.com, 25 Nov 2004 [Full text]

Re: Replicating findings from Guinea-Bissau?

Jayne LM Donegan
bmj.com, 1 Dec 2004 [Full text]

Online poll

Find out more>>