This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to consider undertaking additional work on this program in the future.
- What is the program? Seasonal malaria chemoprevention (SMC) involves giving children under the age of 5 full malaria treatment courses intermittently during the malaria season.
- What is its evidence of effectiveness? Seven randomized controlled trials provide strong evidence that this program reduces cases of malaria. We do not believe that strong evidence exists demonstrating that this program succeeds when implemented at scale.
- How cost-effective is it? SMC programs appear to be in the range of cost-effectiveness of our other priority programs.
- Does it have room for more funding? It appears that there is a large remaining global need for additional funding for SMC programs, but we have not yet done a careful analysis of the funding landscape and other potential funders.
- Bottom line: This program appears promising, and we plan to continue our investigation.
Published: November 2016
Published: November 2016
What is the problem?
Malaria is one of the leading causes of child deaths in Africa.1 It is transmitted from person to person by infected mosquitoes.2 It involves flu-like symptoms including fever.3 As discussed below, there is evidence connecting malaria with death (particularly in children under 5), anemia, splenomegaly (enlarged spleen), other nutrition-deficiency-related indicators, and low birthweight.
It is also believed that malaria can cause permanent disability (hearing impairment, visual impairment, epilepsy, etc.).4
What is the program?
The World Health Organization (WHO) defines seasonal malaria chemoprevention as "the intermittent administration of full treatment courses of an antimalarial medicine to children during the malaria season in areas of highly seasonal transmission."5 It "consists of administering a maximum of four treatment courses of SP [sulfadoxine–pyrimethamine] + AQ [amodiaquine] at monthly intervals to children aged 3–59 months in areas of highly seasonal malaria transmission"6 and "during the high malaria transmission period."7 SMC was "formerly known as ‘intermittent preventive treatment of malaria in children [IPTc].'"8
According to the World Health Organization (WHO):
- where more than 60% of the annual incidence of malaria occurs within 4 months;
- where there are measures of disease burden consistent with a high burden of malaria in children (incidence ≥ 10 cases of malaria among every 100 children during the transmission season)
- where SP and AQ retain their antimalarial efficacy.9
According to the WHO, "SMC provides protection for up to 1 month after each complete (3-day) course…. Health workers should give the dose of SP and the first dose of AQ to the children under their direct observation and should advise the children’s caregivers on how to give the second and third doses of AQ to the child at home."10
Does the program have strong evidence of effectiveness?
A 2012 Cochrane Collaboration review concluded, "In areas with seasonal malaria transmission, giving antimalarial drugs to preschool children (age [less than] 6 years) as IPTc during the malaria transmission season markedly reduces episodes of clinical malaria, including severe malaria. This benefit occurs even in areas where insecticide treated net usage is high."11 Our impression is that there is no evidence demonstrating that SMC has been successfully implemented at larger scale (e.g., across an entire country).
The Cochrane review summarizes the results of seven randomized controlled trials (RCTs). It states:
Seven trials (12,589 participants), including one cluster-randomized trial, met the inclusion criteria. All were conducted in West Africa, and six of seven trials were restricted to children aged less than 5 years. IPTc prevents approximately three quarters of all clinical malaria episodes (rate ratio 0.26; 95% CI 0.17 to 0.38; 9321 participants, six trials, high quality evidence), and a similar proportion of severe malaria episodes (rate ratio 0.27, 95% CI 0.10 to 0.76; 5964 participants, two trials, high quality evidence). These effects remain present even where insecticide treated net (ITN) usage is high (two trials, 5964 participants, high quality evidence).
IPTc probably produces a small reduction in all-cause mortality consistent with the effect on severe malaria, but the trials were underpowered to reach statistical significance (risk ratio 0.66, 95% CI 0.31 to 1.39, moderate quality evidence). The effect on anaemia varied between studies, but the risk of moderately severe anaemia is probably lower with IPTc (risk ratio 0.71, 95% CI 0.52 to 0.98; 8805 participants, five trials, moderate quality evidence). Serious drug-related adverse events, if they occur, are probably rare, with none reported in the six trials (9533 participants, six trials, moderate quality evidence).
Amodiaquine plus sulphadoxine-pyrimethamine is the most studied drug combination for seasonal chemoprevention. Although effective, it causes increased vomiting in this age-group (risk ratio 2.78, 95% CI 2.31 to 3.35; two trials, 3544 participants, high quality evidence). When antimalarial IPTc was stopped, no rebound increase in malaria was observed in the three trials which continued follow-up for one season after IPTc.12
We also identified two RCTs that were published after the Cochrane review.13 We have not reviewed these carefully.
Our impression is that there is no evidence demonstrating that SMC has been successfully implemented at larger scale (e.g., across an entire country). The ACCESS-SMC Partnership, "a UNITAID-funded project led by Malaria Consortium in partnership with Catholic Relief Services (CRS)," that focuses on supporting SMC services in seven countries in Africa lists "Demonstrate effectiveness and safety of SMC implementation at-scale" as one of its primary goals, leading us to believe that the effectiveness of SMC implementation at-scale has not yet been demonstrated.14
How cost-effective is the program?
SMC programs appear to be in the range of cost-effectiveness of our other priority programs. See our most recent cost-effectiveness model for estimates of the cost per life saved through Malaria Consortium-supported SMC programs. See our Malaria Consortium review for more details on the cost-per-treatment for SMC.
Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. For example, our model does not include the short-term impact of non-fatal cases of malaria prevented. It also does not include possible offsetting impacts or other harms.15
There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally, due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.
Does the program appear to have room for more funding?
The ACCESS-SMC Partnership, "a UNITAID-funded project led by Malaria Consortium in partnership with Catholic Relief Services (CRS)," that focuses on supporting SMC services in seven countries in Africa,16 estimated that in 2016 54% of the children eligible for this program (across the seven countries where it worked) would not be reached,17 and the total cost of filling the unmet need for 2016 was approximately $49 million.18
For more information on the global need for treatment and other potential funders of this program, see this section of our Malaria Consortium review.
Organizations that implement this program
We have not attempted to identify all organizations that implement SMC. Organizations that run this program include:
Focus of further investigation
Below, we list areas we expect to research when we revisit this intervention:
- Evidence of effectiveness:
- Additional RCTs published since 2012. As noted above, we have not yet incorporated the results from trials completed after the Cochrane review was published into our analysis.
- Heterogeneity of results in trials. Cochrane reports three different measures of heterogeneity (Tau2, Chi2, and I2) for SMC's effect on clinical malaria episodes. We have not yet considered these carefully, but they appear to be consistent with significant heterogeneity in results.21
- Lack of mortality effect. As noted above, the trials did not find a statistically significant effect on all-cause mortality. We have not carefully considered how this should affect our conclusion.
- Interaction with malaria nets. We have not attempted to carefully model the fact that SMC and malaria nets may be expanded in the same location at the same time. This could reduce each intervention's cost-effectiveness.
- Target coverage rate. The WHO recommends that "the method of delivery must be such that > 95% of eligible children receive SMC at monthly intervals during the period of highest malaria risk."22 We have not attempted to analyze whether the cost-effectiveness of the intervention would be significantly lower if an organization implementing the program did not meet this target.
- Impact on drug resistance. Mass delivery of these medicines could lead to increased drug resistance. We have not attempted to incorporate this possible negative effect into our analysis.
We reviewed the Cochrane Collaboration review (discussed above), the ACCESS-SMC website, the section of the WHO website devoted to SMC, and some documents provided to us by Malaria Consortium.
"In 2015, malaria was the fourth highest cause of death, accounting for 10% of child deaths in sub-Saharan Africa." World Health Organization. World Malaria Report (2015), Pg x.
"Human infection begins when the malaria vector, a female anopheline mosquito, inoculates plasmodial sporozoites from its salivary gland into humans during a blood meal. The sporozoites mature in the liver and are released into the bloodstream as merozoites. These invade red blood cells, causing malaria fevers. Some forms of the parasites (gametocytes) are ingested by anopheline mosquitoes during feeding and develop into sporozoites, restarting the cycle." Jamison et al. 2006, Pg 413.
"Most malaria infections cause symptoms like the flu, such as a high fever, chills, and muscle pain. Symptoms tend to come and go in cycles. Some types of malaria may cause more serious problems, such as damage to the heart, lungs, kidneys, or brain. These types can be deadly." WebMD. Malaria: Topic overview.
See Jamison et al. 2006, Pg 416, Table 21.3 for estimates of cases of hearing impairment, visual impairment, epilepsy, etc. caused by malaria.
Meremikwu et al. 2012, Pg 2.
Meremikwu et al. 2012, Pg 2.
See our most recent model, "SMC" and "Results" sheets.