3
Immunization Programs

The Expanded Programme on Immunization (EPI), with recommended guidelines established by the World Health Organization, is a major international effort to increase the proportion of children covered by basic immunizations against childhood diseases. Because of Africa's unusually high rates of child mortality from measles, the prevalence of tuberculosis, and in many places, substantial mortality due to neonatal tetanus, EPI plays a central role in the health strategy for Africa. In addition, the low levels of funding for health programs in Africa have forced many countries to focus their scarce resources on what are perceived as the most cost-effective interventions, which include EPI (Walsh and Warren, 1979).

In general, the vaccines that form the core of EPI programs are measles, diphtheria-pertussis-tetanus, poliomyelitis, bacille Calmette-Guérin (BCG) for tuberculosis, and tetanus for pregnant women or women of childbearing age. Each of these vaccines has been proven efficacious to varying degrees. However, vaccine efficacy does not necessarily imply that a program based on vaccinations is effective in reducing mortality. There are two reasons that programs might be less effective than suggested by the efficacy of the vaccines. First, as pointed out in Chapter 2, child mortality in Africa often results from the interaction of several diseases, frequently including malnutrition (although malnutrition, in many cases, may be a consequence of infectious and parasitic diseases). The interactions among different childhood diseases are so complex that it is difficult to estimate the effect of reducing the incidence of a single disease by using mathematical simulations.



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3 Immunization Programs The Expanded Programme on Immunization (EPI), with recommended guidelines established by the World Health Organization, is a major international effort to increase the proportion of children covered by basic immunizations against childhood diseases. Because of Africa's unusually high rates of child mortality from measles, the prevalence of tuberculosis, and in many places, substantial mortality due to neonatal tetanus, EPI plays a central role in the health strategy for Africa. In addition, the low levels of funding for health programs in Africa have forced many countries to focus their scarce resources on what are perceived as the most cost-effective interventions, which include EPI (Walsh and Warren, 1979). In general, the vaccines that form the core of EPI programs are measles, diphtheria-pertussis-tetanus, poliomyelitis, bacille Calmette-Guérin (BCG) for tuberculosis, and tetanus for pregnant women or women of childbearing age. Each of these vaccines has been proven efficacious to varying degrees. However, vaccine efficacy does not necessarily imply that a program based on vaccinations is effective in reducing mortality. There are two reasons that programs might be less effective than suggested by the efficacy of the vaccines. First, as pointed out in Chapter 2, child mortality in Africa often results from the interaction of several diseases, frequently including malnutrition (although malnutrition, in many cases, may be a consequence of infectious and parasitic diseases). The interactions among different childhood diseases are so complex that it is difficult to estimate the effect of reducing the incidence of a single disease by using mathematical simulations.

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The second problem is that vaccines may be less effective in large-scale programs than in small-scale trials of their efficacy. If vaccines are stored incorrectly, used after their expiration date, not given at the appropriate age, or given to children who have already contracted a disease, the effectiveness of the immunization program can be greatly reduced. For these reasons, it is necessary to measure the actual effects of real programs. The EPI programs in most African countries have achieved large increases in the proportion of children who receive all of the standard vaccinations. Figure 3-1 shows the proportions of children aged 12-23 months that had received all the standard vaccinations, based on data from the Demographic and Health Surveys conducted in the mid- to late 1980s. Given the relatively high levels in some countries, it is possible that these programs have had a substantial effect on infant and childhood mortality. Because most of the increase in vaccination coverage occurred after 1985, many of the children born shortly before the survey have a higher likelihood of being vaccinated than their older siblings. However, the effect of these programs on child mortality may be too recent to be evident in the available demographic data for most countries. Moreover, although the trends in immunization coverage are upward, coverage can vary greatly on FIGURE 3-1 Proportion of fully immunized children 12-23 months of age, selected sub-Saharan African countries. NOTE: Based on immunization cards and mothers' recall. BWA—Botswana, BDI—Burundi, GHA—Ghana, KEN-Kenya, LBR—Liberia, MLI—Mali, NGA—Nigeria, SEN—Senegal, UGA—Uganda, ZMB—Zambia, ZWE —Zimbabwe. SOURCE: Demographic and Health Survey reports (see Appendix B).

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a year-to-year basis, especially among programs depending on special vaccination programs. Generally, statistics gathered for the EPI program at the national level focus on specific immunizations rather than the proportion of fully immunized children. The goal of the African Region EPI program for 1990 was to make immunizations available for all infants and to achieve coverage of at least 75 percent for all six EPI vaccines. As of August 1991, the immunization coverage for children 12 to 23 months of age in Africa was estimated to have reached 79 percent for BCG, 57 percent for the third dose of the diphtheria-pertussis-tetanus (DPT) vaccine, 56 percent for the third dose of the oral poliomyelitis vaccine, and 54 percent for the measles vaccine. Although the goals have not yet been achieved, comparison with coverage in 1982 of approximately 28 percent for BCG, 21 percent for poliomyelitis, and 18 percent for measles suggests that vaccination coverage has increased greatly as the EPI program became activated (Expanded Programme on Immunization, 1992). The following sections examine the evidence that vaccination programs against measles, pertussis, tuberculosis, and tetanus have reduced child mortality. Most of the research on EPI programs has focused on measles. The reasons for this emphasis include the high mortality rates from measles, its relative ease of diagnosis, and the potential of program failure because of improper vaccine handling. Much less research exists on pertussis, tuberculosis in children, and tetanus. However, there are several indications of the potential effects of these programs. We have not reviewed the literature on two of the EPI diseases: poliomyelitis and diphtheria. We have not included polio because of the low number of deaths from this disease. However, several African studies suggest that poliomyelitis vaccination campaigns can reduce the incidence of disease and paralysis (Rodrigues, 1991; Deming et al., 1992), despite the vaccine's lower efficacy in Africa than in developed countries (Oduntan, 1978; Böttinger et al., 1981; Expanded Programme on Immunization, 1990; de Swardt et al., 1990). Diphtheria has a low incidence rate in sub-Saharan Africa because of high levels of acquired immunity, but can have a high case-fatality rate (Rodrigues, 1991). This immunity may be due to widespread, relatively mild, subclinical cases. Among children diagnosed with diphtheria, the case-fatality rate is high. Relative to other diseases, diphtheria is apparently not a major cause of death among African children. One study suggests that DPT vaccination in Sudan has reduced the incidence of diphtheria (Loevinsohn, 1990). We know very little about the role of diphtheria in African mortality because no reliable sources of community-based data exist, nor is there information about the contribution of diphtheria vaccine to the effect of vaccination programs in Africa (Rodrigues, 1991).

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Several vaccines that are included in immunization programs in some parts of the African continent are not reviewed here. In particular, yellow fever and meningitis vaccines are used to control epidemics in parts of West Africa. MEASLES As discussed in the introduction to this chapter, measles is one of the leading causes of infant and child mortality in sub-Saharan Africa. Here, we review the state of knowledge on measles. We begin with a discussion of the epidemiology and vaccine efficacy. A discussion on why Africa may be different from other parts of the world with respect to measles follows. Measles immunization programs are then examined, with a focus on their effects, the relationship between immunization coverage and measles mortality, and program history and coverage. Finally, treatment strategies are discussed. EPIDEMIOLOGY Measles is caused by a paramyxovirus called morbilli. It is highly infectious and transmitted from person to person via droplet spread (sneezes or coughs) or through direct contact with nasal or throat secretions of infected persons. The incubation period of approximately 10 to 12 days is followed by cough, nasal congestion, and conjunctivitis. The characteristic rash appears about two to four days after the onset of other symptoms. The total illness generally lasts 7 to 10 days (Orenstein et al., 1986). A case of measles provides lifetime protection, and repeat cases are rare. The symptoms of the disease are well known in Africa, and there are local names for it in many languages. Common complications include otitis media (inner ear infections), laryngitis, pneumonia, diarrhea, and encephalitis. Measles is one of the major causes of death among children in Africa. It is a contributing factor in 8 to 10 percent of deaths among African children (Ofosu-Amaah, 1983; Rodrigues, 1991). The proportion is even higher in many parts of the continent. For example, a study in Senegal in 1963-1965 found that measles deaths accounted for 26 percent of deaths among children ages 1 to 4 and 19 percent of all deaths under age 5 (Cantrelle, 1968). During epidemic years, measles can be responsible for 50 percent of all deaths at ages 1 to 4 years (Garenne and Cantrelle, 1986). Because measles often leads to severe diarrhea or respiratory infections, it is probably an underlying cause of many more child deaths. For example, a study in Bangladesh (Clemens et al., 1988) found that measles vaccination reduced the odds of dying from diarrhea by 59 percent, the odds

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from respiratory illness by 22 percent, and the odds from malnutrition (i.e., ''swelling or edema") by 47 percent. Feachem and Koblinsky (1983) listed measles immunization as one strategy for reducing child mortality from diarrheal diseases. They calculated that measles immunization at the age of 9-11 months, with coverage of 45 to 90 percent might avert 6-26 percent of diarrhea deaths among children less than 5 years of age. Although respiratory and gastrointestinal infections often occur during or in the month after measles cases, excess mortality can continue for many months. Hull et al. (1983) followed children who had measles and compared their overall mortality with that of children who did not have measles. Half of the extra deaths among children who had measles occurred three to nine months after the case. Therefore, studies that ascribe death in the one to three months following a case as measles deaths may be understating the true effect of measles on mortality rates. One possible explanation for the long-term effect of measles is the growth retardation that often follows. The Kasongo Project Team (1986) documented that three months after the onset of measles, growth retardation was still apparent based on both weight-for-age and weight-for-height relative to local standards, as discussed in Chapter 5. Another possible explanation is an alternation of physical defense mechanisms or a decrease in immunocompetence because of the measles virus. VACCINE EFFICACY There are several measles vaccines in use today. The most common in Africa is the Schwarz vaccine, an attenuated live vaccine introduced in 1966. During the 1980s, this and other measles vaccines were modified to increase their stability and, thereby, their effectiveness. A second vaccine, the Edmonston-Zagreb, has recently been tested in high doses as a way of lowering the standard age at which the vaccination can be given. Several studies, most of them prospective studies based in communities, have estimated the efficacy of measles vaccine, which is its ability to prevent measles when used in carefully controlled trials. In a recent clinical trial conducted in Senegal, the efficacy of the Schwarz measles vaccine given at 10 months of age was 98 percent (the 95 percent confidence interval (C.I.) was 86-100 percent; Garenne et al., 1992). A study by Hull et al. (1983) estimated that measles vaccine efficacy in The Gambia was 89 percent in children more than 9 months of age (95 percent C.I. 77-94 percent). Lamb (1988) estimated an efficacy of 90 percent for The Gambia. These estimates are close to those from Europe and North America (e.g., Miller, 1987; Rebiere et al., 1990). However, a study by Aaby et al. (1990b) estimated a lower vaccine efficacy of only 46 percent (95 percent C.I. 7-69 percent) in Bandim district

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in Guinea-Bissau, among children born in 1984-1985. Even after assuming that the vaccine was not effective until 35 days after the injection, they still estimated that its efficacy was only 68 percent (95 percent C.I. 39-84 percent). This low efficacy was not due to vaccine failure since antibody tests of vaccinated children showed rates of seropositivity greater than 95 percent. It is also unlikely that this low estimate is a result of either misclassification of vaccination status or inappropriate age at vaccination. The effectiveness of measles vaccines may be lower in field conditions than in carefully conducted studies because of inappropriate storage of the vaccine (cold chain failures), inappropriate age at vaccination, or other incorrect vaccination procedures (e.g., Cutts et al., 1990a). A recent study of children vaccinated at the Institute of Child Health at University College Hospital in Ibadan, Nigeria (Adu et al., 1992) suggests that vaccine effectiveness might be a serious problem. Only 55 percent of children seroconverted after vaccination, and 87 percent of these had low antibody levels. The vaccines came from four different manufacturers and nine batches. The authors suggested that this low efficacy may have been a result of cold chain failures. Attempts to measure effectiveness of large immunization programs are complicated by problems in verifying both vaccination status and measles cases. For example, a study in Mozambique found that adjustments for the estimated accuracy of mother's reports of measles cases raised the estimated vaccine efficacy from 37 to 66 percent (Cutts et al., 1990a). A similar study in Tanzania found an efficacy of 54 percent based on mother's recall of vaccination status compared to an estimate of 96 percent based on clinic cards (Killewo et al., 1991). Garenne et al. (1992) used health cards, as well as clinical and serological records, to estimate the efficacy of vaccines delivered by the national vaccination campaigns in the study area of Niakhar, Senegal, in 1986-1987. They estimated the vaccine efficacy for those children immunized at 86 percent (95 percent C.I. 77-92 percent). This estimate represents a failure rate five times greater than that found in clinical trials using the same vaccine in the same area. Porter et al. (1990) examined vaccine efficacy in five refugee camps in Malawi. They based their calculations on the vaccination status of children who had a health card (which indicates immunizations definitely received) and estimated efficacy to be greater than 90 percent. These studies suggest that vaccine efficacy is very high in Africa in carefully controlled studies. However, in programs, vaccine failure can be a serious problem. Therefore, we cannot simply assume that high coverage rates necessarily imply that large proportions of children are protected against measles. There are some studies in other continents that demonstrate the effectiveness

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of measles vaccination in reducing mortality. For example, a study in Bangladesh (Koenig et al., 1990) found that mortality among vaccinated children ages 9 to 60 months was about 40 percent lower than among a matched group of unvaccinated children. This difference remained after controlling for differences in socioeconomic status and after several tests for selectivity in the acceptance of vaccination.1 WHY AFRICA MIGHT BE DIFFERENT Measles is a more significant factor in child mortality in Africa than in other areas of the world. One reason for this higher significance is that the high fertility rates in Africa quickly replenish the population of children who have not had measles. In cities, this replenishment leads to frequent epidemics and a younger mean age of cases than was true in Europe before the availability of measles vaccine. Differences in residence patterns between Africa and other areas of the world, with extended families living in enclosed areas in some parts of Africa, can lead to higher case-fatality rates (see below). Estimates of the case-fatality rate for measles suggest that it is unusually severe in some parts of West Africa (Aaby, 1988). The high case-fatality rate is probably not due solely to the young age distribution of cases because the epidemic in southwestern Ethiopia also exhibited very high case-fatality rates, despite 22.6 percent of cases having occurred among children aged 5 to 10 years and 5.9 percent in children 11 years or older (Lindtjorn, 1990). Although the high prevalence of malnutrition is often mentioned as a reason for high case-fatality rates, the evidence is inconclusive (see discussion of nutrition and measles in Chapter 5). It is likely that the high case-fatality rates are related to the low level of health services available in many areas and the high proportion of secondary cases in households (discussed in detail below). Another feature of measles in Africa is that measles vaccination is effective at earlier ages than is true in developed countries because maternal antibodies wane earlier in African children. This reduction in immunity is 1   The analysis conducted by Koenig et al. was based on a study carried out by Phillips et al. (1984) in which measles vaccination was offered in March 1982 to all children 9 months of age or older in two (Blocks A and C) of four intervention subareas. In November 1985, measles vaccination was expanded to the remaining two blocks (Blocks B and D). The analysis by Koenig et al. consists of all children in Blocks A and C who were immunized between 9 and 60 months during the period March 1982 to October 1985. These children were randomly matched with unvaccinated children in Blocks B and D, based on: (1) having no record of being vaccinated for measles during the study period; (2) being born in the same month and year as the corresponding matched vaccinee; and (3) the nonvaccinee having survived at least to the date of vaccination of the matched vaccinee.

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apparently due to lower levels of maternal antibodies and less efficient transport of antibodies to the fetus (Black et al., 1986). There is some evidence that children born to mothers who are positive for human immunodeficiency virus (HIV) may have even poorer transport of measles antibodies and a higher risk of measles infection before age 9 months than other children (Embree et al., 1992). The recommended age for vaccination is 9-11 months for tropical Africa, compared to 12-15 months for Europe and the United States (Kenya Ministry of Health and World Health Organization, 1977; Expanded Programme on Immunization, 1982). In some areas, programs have lowered the age for measles vaccination to 6 months. In a study in The Gambia, the efficacy dropped to 37 percent when administered at 6-8 months of age (Hull et al., 1983). Therefore, regular vaccination before 9 months of age is generally not recommended unless it is possible to provide a second does after age 9 months. Studies of the use of high-titer vaccines (i.e., vaccines with high levels of the attenuated virus) on younger children (4-6 months) show reasonable levels of seroconversion and efficacy in preventing measles cases (Whittle et al., 1984, 1988; Aaby et al., 1988b), but low efficacy in reducing mortality (Garenne et al., 1991). EVIDENCE OF MORTALITY AND MORBIDITY EFFECTS FROM AFRICA There are quite a few studies of the effect of measles vaccination on both mortality and the incidence of disease in Africa. The following sections first review the evidence that vaccination against measles can reduce mortality in Africa, then the evidence that programs have reduced the incidence of measles cases. There are several studies that examine the effect of measles vaccination on child mortality rates in sub-Saharan Africa. These studies can be divided into two groups: (1) studies that measure the effect of regular measles immunization programs on mortality, and (2) studies of effects in model programs limited to special research areas. The former evaluations are closer to our main interest because they examine the effect of large-scale programs. The second group of studies demonstrates what can be accomplished in carefully managed programs. These studies provide evidence of the relationship between changes in the incidence of measles and reductions in overall child mortality. Effects of General Measles Immunization Programs Garenne et al. (1985) studied the effect of the national vaccination program in Senegal. The program increased coverage with measles vaccine

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nationally from a few percent in the early 1960s to 74 percent for 1967 and 1968. After 1968, coverage dropped for several years. Garenne et al. (1985) provided data showing that the annual number of measles cases reported nationally dropped by 35 percent in 1967-1971 compared to 1963-1966, corresponding to the national vaccination campaign in 1967-1969. They also show that the proportion of deaths ascribed to measles decreased substantially in the two rural study areas of Ngayokhème and Ndemène (among deaths at ages 0-14 years) and in Dakar (deaths at all ages). After a brief drop, vaccination coverage in Senegal remained greater than about 75 percent nationally for 1974-1979 (Garenne et al., 1985). Even so, the number of children seeking medical attention for measles returned to high levels. In addition, the proportion of child deaths due to measles returned to high levels for 1972-1978 in Ngayokhème and Ndemène, areas covered by continuous registration of deaths. Two studies in Guinea-Bissau, one in an urban area (Bandim; Aaby et al., 1984b) and one in a rural area (Quinhamel; Aaby et al., 1984a), were natural experiments brought about by the introduction of measles vaccination in preexisting research areas. In Bandim, the mortality rate among children aged 6-35 months was 127 deaths per 1,000 in 1979. After a measles vaccination campaign, the rate dropped to 47 in 1980 and 48 in 1981. During 1980 and 1981, the mortality rates for vaccinated children were much lower than the rates among unvaccinated children (Aaby et al., 1984b). Mortality was also lower among vaccinated children than among children who had previously had measles. In Quinhamel, the rates were 107 per 1,000 in 1979 and 98 per 1,000 in 1980. After a measles vaccination campaign in early 1981, the rate was 44 among the vaccinated and 72 among the unvaccinated (Aaby et al., 1984a). Quinhamel was the only one of five rural areas studied where measles was a problem during the study period (Aaby, 1988). Effects of Measles Vaccinationin Field Trials and Model Programs There have been several field trials in defined study populations that were specifically designed to measure the effects of vaccination on mortality. In addition, several model programs have demonstrated the potential of programs. These studies offer more information than vaccine trials because they provide estimates of both the direct and the indirect effects of vaccination. In particular, the measured effects from these studies include the reduction of mortality from diarrhea, respiratory infections, and malnutrition. In vaccine trials, some of these deaths would not be recognized as resulting from measles. If continued for a sufficiently long time, these studies also can show changes in the frequency of epidemics and the resulting

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change in the age distribution of cases. Similarly, these studies are often superior to evaluations of general health programs since they are often based on more scientific study designs. For example, they can include control areas, randomization, or estimation of the effect of the program on those who actually received services. However, these special studies can present a misleading picture of the likely effect of real programs. One reason is that large-scale programs rarely match the high level of supervision and training achieved in smaller programs. It is possible, therefore, that large-scale programs might have more cold chain failures and be less likely to reach the most vulnerable parts of the population. A second reason is that it is easier to carry out field trials in populations where measles is a frequent health problem. In particular, it is not feasible to test the effect of a measles program in an area that experiences measles epidemics only every three to five years. It is also more difficult to carry out these studies in urban areas because of high rates of population mobility. Finally, areas used in research studies often have better access to general health services than other rural areas. Vaccine Field Trial in Khombole, Senegal Garenne and Cantrelle (1986) estimated the efficacy of the Schwarz vaccine using data from field trials in Khombole, Senegal, in 1965-1968. They found that the proportion dying between ages 6 months and 10 years was 26 percent lower among children in the area receiving vaccinations than among children in the control area. It is possible that these results might be affected by other factors related to the selection of the children who were vaccinated. Vaccinations were offered to all children in the vaccination zone. Sixty percent of eligible children were vaccinated in 1965 and 86 percent were vaccinated in 1967. However, because of the nature of the program and the lack of large socioeconomic differentials within the study population, it is unlikely that the results are an artifact of selectivity. Kasongo Project in Zaire The Kasongo Project Team (1981) compared mortality in two areas of rural Zaire. In one area, a measles vaccination program achieved a coverage rate of 83 percent among the cohort born between September 1974 and October 1975.2 In the test area, the mortality rate between 7 and 35 months 2   Measles vaccination was offered to 306 children, of whom 83 percent accepted and were vaccinated. However, the proportion of child-months of observation that were protected by immunization was much lower. The estimated coverage was only 58 percent based on a comparison of the person-months of observation for the program area (their group 1) and for the vaccinated children in the program area (group 1v).

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of age was 95 deaths per 1,000 for the unvaccinated cohort born between June 1973 and August 1974. The rate dropped to 48 per 1,000 for the cohort covered by the vaccination program. In the control area, the rate fell from 80 to 69 over the same period. Therefore, mortality was reduced by 36 deaths per 1,000 more in the vaccination area than in the control area, a difference that was not statistically significant. The Kasongo Project Team suggested that the gains from vaccination appeared to have been reversed at later ages. This conclusion is not warranted by the data they present. Mortality at ages 22-35 months of age increased by 7 per 1,000 in the control area but by only 1 per 1,000 in the vaccination area. These estimates were not significantly different. Data for children beyond age 36 months are not presented. Pahou Primary Health Care Project, Benin The Pahou project measured the effect of primary health care services established in 16 villages 30 kilometers from Cotonou, Benin. Velema et al. (1991) matched each child who died between 4 and 35 months of age with up to four controls of the same age and sex from the same village. A comparison of the vaccination status of cases and controls showed that children vaccinated before 12 months of age experienced a relative risk of death between 4 and 35 months of 0.36, compared to nonvaccinated children (95 percent C.I. 0.16-0.81 times). 3 However, vaccination after 12 months of age was not associated with reduced mortality (relative risk: 1.02 times, 95 percent C.I. 0.43-2.41 times). These results remained after the addition of controls for socioeconomic status, nutritional status, and other measures of the effect of primary health care. These data cannot be used to estimate the change in mortality associated with vaccination because the study did not provide mortality rates for the population.4 Estimates of Effect from Cases of Vaccine Failure A study in Guinea-Bissau by Aaby et al. (1989) compared children who seroconverted after measles vaccination with a group for whom the vaccination 3   Vaccinations in control children after the age at death of the cases were not included in the analysis. 4   The "overall mortality rate" quoted in the article is not a true population mortality rate since it is based only on cases and controls. This rate is therefore an artifact of the number of controls (surviving children) chosen per case (deceased children).

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FIGURE 3-6 Proportions of children aged 12-23 months who have received BCG vaccination, countries of sub-Saharan Africa, 1981 and 1991. SOURCES: 1981 data from United Nations Children's Fund (1991); 1991 data from International Science and Technology Institute (1990) and Expanded Programme on Immunization (1992).

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SUMMARY The prevalence of tuberculosis in Africa is estimated to be 34 percent. Given the link between AIDS and tuberculosis, it is likely that the prevalence of tuberculosis will continue to increase. The BCG vaccination, although of varying and questionable efficacy, has been shown to be effective against both tuberculosis and leprosy in Africa. However, given the great variation in efficacy across continents, it would be useful to have more studies in different African settings. Programs that provide BCG have probably saved many lives and reduced morbidity. However, no precise estimates of the effect of BCG on mortality exist. Childhood deaths that have tuberculosis as an underlying cause may actually outnumber the deaths directly attributed to the disease. Therefore, it is not possible to produce an accurate estimate of the likely effect of the increase in BCG coverage on child mortality in Africa. TETANUS Tetanus is a major cause of neonatal death in much of Africa, as well as among other age groups. Because of the small proportion of the population protected by immunization at all but childhood ages, and the large proportion of births that occur under poor hygienic conditions related especially to home deliveries, tetanus mortality rates in Africa are probably among the highest in the world. The tetanus mortality rate is best documented for neonates—the population in which the problem predominates. Tetanus of the umbilicus is responsible for a substantial proportion of neonatal and infant mortality in many regions where most deliveries are performed by untrained traditional birth attendants or relatives. EPIDEMIOLOGY The few available studies suggest that rates of 10 to 20 neonatal tetanus deaths per 1,000 live births are not unusual. Studies in rural parts of Sierra Leone have led to estimates as high as 70 per 1,000 (Kandeh, 1986). Tetanus may be less of a problem in southern and eastern Africa than in western Africa. The Machakos project in Kenya recorded a rate of only 1.2 per 1,000 (van Ginneken and Muller, 1984). Some studies of tetanus are apparently biased by underreporting of neonatal deaths. This bias is particularly important for estimates based on retrospective reporting of deaths. In several studies, underreporting is apparent in the trends of tetanus mortality rates. In particular, several surveys show higher rates for the months closer to the survey date (e.g., Stanfield

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and Galazka (1984) and Sokal et al. (1988) in Côte d'Ivoire; Expanded Programme on Immunization (1983) in Malawi; however, Melgaard et al. (1988) report no trend in Kenya). On the other hand, estimates of tetanus mortality may be biased upward by errors in diagnosis. For example, Snow et al. (1992) compared verbal autopsies with records of hospital deaths. They found that verbal autopsies performed rather well for neonatal tetanus deaths (sensitivity of 90 percent and specificity of 79 percent). These led to an exaggeration of the neonatal tetanus mortality rate of about 30 percent. More sophisticated treatment of tetanus cases is not currently a viable policy option because such treatment is expensive and difficult. The case-fatality rate of hospitalized cases of neonatal tetanus is usually 60-80 percent (Bwibo, 1971; Kenya Ministry of Health, 1978; Merhai and Kumar, 1986; Maru et al., 1988; Babaniyi and Parakoyi, 1989; Einterz and Bates, 1991). There are fewer data on tetanus after the first month of life. In Kenya in 1978, the case-fatality rate among inpatient cases was 33 percent for children 1-14 and 47 percent for adults over age 15 (Kenya Ministry of Health, 1978). A study in Tanzania reported a lower case-fatality rate among neonates treated with antitetanus equine serum (Mongi et al., 1987). However, a recent meta-analysis (which included the study by Mongi et al.) did not find convincing evidence that this approach improved survival among neonates with tetanus (Abrutyn and Berlin, 1991). Yet, the effect of serum depends on when it is given. During the first two days of life, it has a beneficial effect; thereafter, it does not (M. Garenne, personal communication, 1992). Although improvements in case fatality are possible, only a small proportion of neonatal cases ever receive hospital treatment (Expanded Programme on Immunization, 1983; Babaniyi and Parakoyi, 1989). For example, in a rural area of Côte d'Ivoire, only 2 percent of neonatal tetanus cases came to the attention of medical authorities (Sokal et al., 1988). During 1979 in Kenya, there were 2,258 outpatient cases and 767 inpatient cases of tetanus at all ages in the 33 districts for which data were available (Kenya Ministry of Health, 1978). Extrapolating to the whole population, the Ministry of Health estimated that there were about 3,300 cases at all ages nationally. In comparison, Melgaard et al. (1988) used data on three districts to estimate that there were about 8,000 to 12,000 neonatal deaths due to tetanus annually in the mid-1980s. It is likely therefore that only a fraction of cases of tetanus ever receive even minimal care. PROGRAMS TO REDUCE THE INCIDENCE OF NEONATAL TETANUS In 1989 the World Health Assembly called for the worldwide elimination of neonatal tetanus by 1995 (World Health Organization, 1990). The

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two policy options are improving delivery practices and providing immunizations. One way to improve deliveries is to increase the proportion of deliveries that occur in hospitals or dispensaries where it is easier to maintain appropriate antiseptic practices. In hospitals and dispensaries, it is also possible to administer tetanus antitoxin to newborns shortly after delivery—a practice common in francophone areas (Sokal et al., 1988). Alihonou (1970) attributes the rapid decline or reported deaths from neonatal tetanus in Dakar to this practice. An alternative approach is to train traditional birth attendants or midwives to improve home deliveries by using sterile instruments for cutting the umbilicus and to treat the stump appropriately. The other option is immunization of pregnant women, which provides temporary immunity to the fetus and protects the newborn for several months. The World Health Organization recommendation is that women receive two injections of tetanus toxoid at least one month apart as early as possible during pregnancy. One study (Owa and Makinde, 1990) suggests that children who do contract neonatal tetanus have a greater chance of survival if their mother has had a single prenatal tetanus injection. A single booster injection is recommended for subsequent pregnancies. Four or five tetanus toxoid vaccinations are likely to provide lifetime protection for the mother and for each of her children during the neonatal period (Wassilak and Berlin, 1986). In areas where neonatal tetanus is a serious problem, vaccination programs should target all women of childbearing age. In practice, most programs include efforts both to improve deliveries and to provide tetanus immunization to women. Although the combination is probably more efficacious than either approach alone, it is difficult to evaluate the independent efficacy of each approach. Only one study has attempted to compare these strategies. Orenstein et al. (1985, quoted in Babaniyi and Parakoyi, 1989), estimated that in Nigeria the efficacy of two doses of tetanus toxoid was higher than that of either hospital delivery or home delivery by a trained midwife. Incidence of Neonatal Tetanus Among Hospital Deliveries Several studies have shown that the incidence of neonatal tetanus is much lower among hospital deliveries than among other births (Dan et al., 1971; Stanfield and Galazka, 1984; Kofoed and Simonsen, 1988; Sokal et al., 1988). Melgaard et al. (1987) reported that in three districts of Kenya the neonatal tetanus mortality rates were 14.1 for home deliveries and 4.3 for deliveries in health institutions. These estimates yield a relative risk of 3.3 associated with home deliveries compared to hospital deliveries. Other studies have found that all recorded cases of neonatal tetanus were among children born at home (e.g., Sokal et al., 1988). Women who deliver in hospitals may be different from other women in many ways (e.g., they are more likely to live in urban areas and may be

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better educated). However, the lower incidence of neonatal tetanus among hospital births also probably reflects better care of the umbilical stump. Even so, hospital delivery is not a guarantee of protection. Even the most careful delivery will not protect the child against treatment of the stump or circumcision practices after the child leaves the hospital. Evidence of the Effect of Training of Traditional Birth Attendants Because of the high cost and unavailability of hospital deliveries for most African women in rural areas, many authorities have recommended training traditional birth attendants (TBAs) in aseptic procedures for cutting the umbilical cord and caring for the umbilical stump. A study by Leroy and Garenne (1991) in rural Senegal suggests that the most important risk factor for neonatal tetanus is whether or not the person who delivered the baby washed her hands with soap prior to cutting the cord. However, most training programs have concentrated on improving the instrument used for cutting the cord. There are very few studies anywhere in the world that provide evidence of the effect of training TBAs on tetanus mortality in populations in which tetanus toxoid coverage did not also increase (Ross, 1986). Studies in the Philippines and Bangladesh have shown that midwife training reduces overall neonatal mortality more than maternal immunization, but maternal immunization alone causes a larger reduction in the incidence of neonatal tetanus than midwife training (Stanfield and Galazka, 1984). There has been one such study in Africa in the Thies region of Senegal. In the first part of the study, birth attendants in six villages learned to care for the cord properly. After this training, the neonatal mortality rate in the program villages was 38 per 1,000 live births, compared to 101 in the control villages (Dan et al., 1971). The recorded postneonatal rates in the two areas were identical (147 and 146 per 1,000). In the years following this study, the program reached an increasing number of villages. Sanokho and Senghor (1975, quoted by Ross, 1986) examined the place of residence of neonatal tetanus cases recorded at the Khombole hospital. The proportion of these cases that were from villages selected for the midwife training program dropped substantially after the start of the program. These studies suggest that the training of traditional birth attendants can reduce the incidence of neonatal tetanus, at least in populations with high rates. Evidence of the Effect of Programs that Provide Tetanus Toxoid Immunization to Women Studies of antenatal immunization against tetanus in other parts of the world have shown that two injections of tetanus toxoid early in pregnancy

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are 95 percent effective in preventing neonatal tetanus in the child born of that pregnancy. The effect of two injections declines over time. Some studies show that the injections are still 40 percent effective in reducing neonatal tetanus four to five years later, and Koenig (1992) reports that two doses of tetanus toxoid may provide protection against neonatal tetanus for 15 years or more. A single booster shot restores the full effectiveness. A single injection during pregnancy provides partial protection for that pregnancy (see summary in Stanfield and Galazka, 1984). Susceptibility to tetanus and case-fatality rates are not affected by the presence of other common diseases (e.g., malaria, malnutrition). Therefore, there is no reason to expect that at a given level of neonatal tetanus mortality and a given level of program coverage, the effect of an immunization program would differ across populations. What is uncertain is the success rate of various types of programs in achieving high levels of effective coverage. In particular, there is little information on the proportion of women who deliver at home after receiving at least two injections of tetanus toxoid. We also do not have studies that suggest what proportion of births are partially protected by tetanus toxoid injections during a previous pregnancy. A few studies in Africa have demonstrated the efficacy of immunization with or without midwife training programs. Ross (1986) reported the results of a program that formed village health teams in 11 villages near Serabu Hospital, Sierra Leone. The program trained TBAs in improved perinatal care and encouraged them to refer pregnant women for antenatal care, which included tetanus toxoid injections. Within a year of the start of the program, the neonatal tetanus mortality rate declined from 72 to 11 per 1,000 live births (this difference is significant at the 0.001 level). In the next few years, the mortality from neonatal tetanus continued to decline to ''virtually zero" (Ross, 1986). The program near Serabu Hospital must be considered a field trial because it is not clear whether that program could be successfully replicated in larger populations. Two studies of large-scale programs that participated in the Combattings Childhood Communicable Diseases (CCCD) project, funded by the U.S. Agency for International Development and carried out by the Centers for Disease Control of the U.S. Department of Health and Human Services, provide some evidence of the efficacy of tetanus immunization on neonatal mortality. In one area of Zaire and two counties in Liberia, the CCCD programs were evaluated by using retrospective maternity histories before and after the start of the program. In Liberia, data on cause of death based on verbal autopsies suggested that there was a reduction of approximately 50 percent in neonatal tetanus mortality (probability less than .05; Becker et al., 1993). This decrease was probably the result of an increase in the proportion of mothers who had received two tetanus toxoid injections from very low levels to more than 30 percent (Vernon et al., 1993). The CCCD

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surveys in Zaire did not include verbal autopsies. However, there was no evidence of a decline in infant mortality. This apparent lack of effect is consistent with the absence of neonatal tetanus cases reported by the local hospital and health centers before the program (Vernon et al., 1993). Because case-fatality rates are so high and few cases receive modern medical care, we can safely use data on disease incidence to monitor programs. A study of neonatal tetanus in Maputo, Mozambique, suggests that a vaccination program alone can have a significant effect in urban areas. Cutts et al. (1990b) reported that from 1976 to 1978, there were between 173 and 254 cases of neonatal tetanus reported annually in Maputo. After the start of the vaccination campaign, the proportion of mothers reporting at least two injections of tetanus toxoid increased to 42 percent in 1982, 91 percent in 1983, and 87 percent in 1986. This increase in vaccination coverage coincided with a rapid decline in the number of reported cases to a range of only 3 to 13 cases per year between 1982 and 1987. Although it is not possible to calculate the mortality effect of this program based on these surveillance data, the program must have been associated with a dramatic drop in neonatal tetanus mortality. In Malawi, immunization of pregnant women with tetanus toxoid began in 1984. Coverage increased from about 27 percent in 1985 to more than 60 percent in 19887 (Expanded Programme on Immunization, 1989). Although the number of neonatal tetanus cases reported in hospitals dropped in 1986 and 1987, the change was not significant. Finally, Sokal et al. (1988) quoted a study by Yada et al. (1981) from Burkina Faso. In one area of the country, coverage with two injections of tetanus toxoid reached 50 percent and hospital admissions for tetanus decreased by two-thirds. PROGRAM COVERAGE Figure 3-7 presents national estimates for 1981 and 1991 of the proportion of recent deliveries in which the woman had at least two injections of tetanus toxoid during pregnancy (International Science and Technology Institute, 1990; United Nations Children's Fund, 1991; Expanded Programme on Immunization, 1992; Nigerian Federal Office of Statistics and Institute for Resource Development, 1992). In 1991, about 41 percent of deliveries were protected by recent tetanus toxoid injections. This coverage is much larger than the value for 1981, which was less than 15 percent. Estimates for West Africa, where neonatal tetanus may be more common, indicate that 7   These figures were read from the graph in the article.

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coverage increased from about 12 to 44 percent. These estimates are subject to numerous types of sampling and reporting error because they are often based on women's retrospective reporting and on sample surveys. In addition, children born to women who received several tetanus toxoid injections during previous pregnancies are partially protected against tetanus. Despite these weaknesses, the data suggest substantial improvements in coverage, although most pregnancies are still not protected. PROGRAMS TO REDUCE NONNEONATAL TETANUS MORTALITY The standard EPI program in most African countries includes tetanus immunization of young children as part of the DPT series. With the high coverage rates achieved in many areas, there have likely been reductions in nonneonatal and pediatric tetanus. However, to our knowledge there have not been any studies of the effect of this aspect of EPI programs. Similarly, antenatal immunization may have reduced tetanus mortality among adult women, but we are not aware of any studies of the effect of these programs on adult mortality. SUMMARY Tetanus is a leading cause of neonatal death in sub-Saharan Africa, with a range of 10 to 20 deaths per 1,000 live births in much of the region prior to control efforts. Lower rates in southern and eastern Africa suggest that regional differentials exist in neonatal mortality, but this result could be due to biases arising from underreporting of neonatal deaths. Programs designed to reduce mortality from neonatal tetanus generally focus on improving delivery conditions (such as training TBAs to incorporate sanitary practices) and immunizations of pregnant women or women of reproductive age. A number of studies conducted in Liberia, Mozambique, and Burkina Faso indicate that as the proportion of pregnant women who are immunized increases, mortality from neonatal tetanus decreases. For a woman to be covered adequately against tetanus, she needs to have received at least two injections of tetanus toxoid at least one month apart as early as possible during the pregnancy (the first time she receives the immunization), with a single booster injection (up to three) given during subsequent pregnancies for the mother and for the child during the neonatal period. Results from the Demographic and Health Survey indicate that a relatively large proportion of mothers of children born during the five years prior to the survey in most countries were adequately immunized against tetanus. Similarly, an association is observed between women being immunized against tetanus

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FIGURE 3-7 Proportions of births preceded by at least two prenatal injections of tetanus toxoid, countries of sub-Saharan Africa, 1981 and 1991. SOURCES: 1981 data from United Nations Children's Fund (1991); 1991 data from International Science and Technology Institute (1990) and Expanded Programme on Immunization (1992).

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and those having hospital-based deliveries. Thus, the women with the greatest likelihood of having unsanitary conditions at delivery are also those who have not received adequate immunization against neonatal tetanus. CONCLUSION The Expanded Programme on Immunization has had a large impact on increasing vaccination coverage. As noted earlier, vaccination coverage for the preventable diseases included in the EPI increased substantially between the 1980s and 1990s, as illustrated by the increase in BCG coverage from 28 to 79 percent and measles vaccination coverage from 18 to 54 percent. Despite the increase in coverage, the quantity and quality of research on the effects of various components of standard EPI immunization programs on child mortality are uneven. Measles has been studied widely in Africa from epidemiological and programmatic perspectives. Programs using the standard age schedule for vaccination with the standard vaccine can be effective in preventing measles and reducing child mortality in Africa by large proportions. Although the vaccine is highly efficacious, studies indicate that in some large-scale programs, cold chain failures have greatly reduced program effectiveness. In some study areas, program effectiveness has varied substantially over time. Although vaccination coverage is increasing, measles is not likely to be eliminated from Africa in the near future. Thus, in addition to the need for continued research on the disease's epidemiology, we need to know more about treatment strategies for children who contract the disease. The vaccination coverage for pertussis has not achieved the EPI program goal of 75 percent; currently, it is estimated to be about 57 percent. Pertussis is difficult to diagnose because it has no uniquely distinguishing symptoms in its early stages. A wide range of estimates of the efficacy of the pertussis component of the DPT series has been reported. The vaccine, however, has reduced the incidence of the disease and may lower the severity of infection among those who are vaccinated and become ill. We do not have any estimates of the effect of DPT on mortality. Tuberculosis is an important cause of mortality and morbidity among both children and adults in Africa, with an estimated prevalence of 34 percent. Its effect among children may be underestimated because it is often a contributing cause, rather than the primary cause of death. The BCG vaccination is of questionable efficacy in preventing cases of tuberculosis—estimates range from 0 to 80 percent—but may be more effective in preventing the more serious forms of the disease. It has also been shown to be effective in preventing leprosy. Tetanus is a leading cause of neonatal mortality in some areas of sub-Saharan

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Africa. It is preventable if the mother has been adequately vaccinated. Other options for reducing the disease are the training of traditional birth attendants in hygienic delivery practices and the administration of tetanus antitoxin to the child shortly after delivery. Before the initiation of the Expanded Programme on Immunization, as recently as the early 1980s, vaccination coverage in Africa was the lowest in the world (Rodrigues, 1991). To augment national programs, acceleration strategies based on outreach components such as mobile units and improved cold chains were implemented in the mid-1980s. Greater attention to these preventable diseases through increased immunization has probably had a large effect on reducing mortality, but the full potential of these programs has not been achieved. Increased coverage with the standard EPI immunizations and maintenance of high coverage should continue to be top priorities for reducing child mortality.