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Background: Intermittent Preventive Treatment for malaria control in infants (IPTi) consists of the administration of a treatment dose of an anti-malarial drug, usually sulphadoxine-pyrimethamine, at scheduled intervals, regardless of the presence of Plasmodium falciparum infection. A pooled analysis of individually randomized trials reported that IPTi reduced clinical episodes by 30%. This study evaluated the effect of IPTi on child survival in the context of a five-district implementation project in southern Tanzania. [Trial registration: clinical trials.gov NCT00152204]. Methods. After baseline household and health facility surveys in 2004, five districts comprising 24 divisions were randomly assigned either to receive IPTi (n = 12) or not (n = 12). Implementation started in March 2005, led by routine health services with support from the research team. In 2007, a large household survey was undertaken to assess the impact of IPTi on survival in infants aged two-11 months through birth history interviews with all women aged 13-49 years. The analysis is based on an “intention-to-treat” ecological design, with survival outcomes analysed according to the cluster in which the mothers lived. Results: Survival in infants aged two-11 months was comparable in IPTi and comparison areas at baseline. In intervention areas in 2007, 48% of children aged 12-23 months had documented evidence of receiving three doses of IPTi, compared to 2% in comparison areas (P < 0.0001). Over the three years of the study there was a marked improvement in survival in both groups. Between 2001-4 and 2005-7, mortality rates in two-11 month olds fell from 34.1 to 23.6 per 1,000 person-years in intervention areas and from 32.3 to 20.7 in comparison areas. In 2007, divisions implementing IPTi had a 14% (95% CI -12%, 49%) higher mortality rate in two-11 month olds in comparison with non-implementing divisions (P = 0.31). Conclusion: The lack of evidence of an effect of IPTi on survival could be a false negative result due to a lack of power or imbalance of unmeasured confounders. Alternatively, there could be no mortality impact of IPTi due to low coverage, late administration, drug resistance, decreased malaria transmission or improvements in vector control and case management. This study raises important questions for programme evaluation design. © 2011 Schellenberg et al; licensee BioMed Central Ltd.
After baseline household and health facility surveys in 2004 [7], the research team developed a strategy for IPTi implementation in partnership with the Ministry of Health during 2004-2005 [4,6]. Twelve of 24 clusters were randomly assigned to receive IPTi, and implementation started in March 2005 led by routine health services with limited support from the research team. The trial profile is shown in Figure Figure1.1. In 2006, a follow-up health facility survey documented the availability of IPTi and staff trained in its delivery, together with an interim household survey to assess IPTi coverage and effects on the prevalence of malaria and anaemia [8]. In 2007, a large household survey which included the entire population was undertaken to assess the impact of IPTi on infant survival. The focus of this manuscript is the analysis of survival and includes process and contextual factors from household surveys to support that analysis. An intention-to-treat approach and an ecological design was used, with survival outcomes analysed according to the cluster in which the mothers lived and being unlinked to individual records of IPTi use. Trial profile. The study area covers five districts, split into 24 administrative divisions, in the Lindi and Mtwara regions of southern Tanzania. Lindi Rural, Ruangwa and Nachingwea districts are in Lindi Region and Newala and Tandahimba are in Mtwara region. The area has a total population of over 800,000 people and the highest reported infant mortality rates in the country [10,11]. Relatively neglected for many years, the infrastructure is weak with poor access to water and electricity. Most people are small-scale subsistence farmers although the area produces most of Tanzania's cashew nuts as a cash crop through small-holder approaches. At baseline in 2004 a representative sample of 21,482 households was identified using a modified EPI cluster sampling strategy, as reported in detail elsewhere [7]. In brief, 30 clusters of 30 households were identified in each division. Where written informed consent was given to interview, data were collected using Personal Digital Assistants (PDAs), enhancing data quality and timely availability of cleaned data [12] in anticipation of randomization of divisions to intervention or comparison groups. Birth histories were done in 19,008 (94%) of the 20,138 women aged 15-49 years reportedly resident in the households. For eight clusters in each division, additional information was collected on children aged under 2 years old about illnesses in the preceding 2 weeks, health-seeking behaviour and the prevalence of anaemia and parasitaemia [7,8]. The 24 divisions were arranged into three strata on the basis of mortality in children aged two-11 months, as measured in the baseline household surveys. Restricted randomization was used to allocate each of the 24 divisions into the IPTi or comparison group so as to assure adequate balance in terms of baseline mortality, overall population size and district health management team [13]. Details are given elsewhere [8]. Briefly, of 343,000 possible ways of allocating 12 divisions to the intervention arm (four within each of the three strata), 11,014 achieved "balance" with respect to mortality, population size and district, and one of these was chosen at random. A detailed description of the development and implementation of the IPTi strategy is given elsewhere [4]. Following development of the IPTi strategy and piloting in two health facilities for a month, staff working in district and regional health teams trained front-line health workers how to implement IPTi in the first quarter of 2005. Subsequent follow-up by the project was limited to a single IPTi-specific health facility visit after training, followed by occasional visits to health facilities when the district health teams undertook routine supervision visits. All visits to health facilities were made in conjunction with members of the district health team. The IPTi-specific "follow-up after training" visits to each facility were completed before 24 May 2005: therefore, 24 May 2005 is used as the start date of the intervention. Monitoring of acceptability, financial and economic costs, the impact on morbidity and the safety of IPTi was established and is reported elsewhere. Four in vivo anti-malarial drug efficacy tests were conducted (one in 2005 and three in 2006), following the standard WHO protocol with 42 days of follow-up. These studies showed 28 day PCR uncorrected adequate parasitological and clinical response rates of 62-63% in three sites and 49% in one site (data not shown), compared with 60% previously documented in the context of an earlier clinical trial which showed IPTi to be highly efficacious [14]. Molecular analysis of samples collected in household surveys showed a 44% frequency of the DHFR triple mutation in 2004, rising to 60% in 2007. The frequency of the 540E mutation (a marker of the quintuple mutation, DHFR triple and DHPS double) was 65% in 2004, 80% in 2006 and 68% in 2007 [unpublished observations]. Health facility and household surveys in 2006 showed that IPTi was available in 94% of intended health facilities and that there was evidence of a biological effect on malaria and anaemia in the target group of children aged two-11 months [8]. The primary aim of this final household survey was to estimate the effect of the IPTi strategy on mortality in children aged two-11 months. Secondary aims included (i) estimation of the coverage of IPTi in a sub-sample of households, and (ii) to assess whether there were any large imbalances between the IPTi and comparison groups in contextual factors including preventive health measures such as mosquito nets and vaccine coverage, nutritional status, case management and care-seeking for recent illness. Such factors were potential confounders of the effect of the IPTi strategy on infant survival. The aim was to include all households in the area, with an expected total of roughly 250,000 and a range from 2,500 to 26,000 households in any one division. On the basis of the baseline survey in 2004, a two-11 month mortality rate of 36.2 per 1,000 person-years was expected, or approximately 463 deaths, in the comparison group, providing 80% power to detect an impact of IPTi of 30% on survival, equivalent to a reduction from 36 to 25 deaths per 1,000 child years [13]. In a clustered subsample of households this sub-study aimed to estimate coverage of IPTi of 50% to within 5% points, assuming a 95% confidence level, that 3.14% of the population is in this age group, an average of 100 households in each cluster, 3.88 people per household, and a design effect of two. Eight sub-villages (vitongoji) were selected from each division with equal probability and more children from larger vitongoji, thus assuring the sample of children was self-weighting within each division. Between 25 June and 30 October 2007, the main survey teams visited all households in the five districts and completed a household module. Women aged 13-49 years had a birth history module completed. Mothers of children < 2 years were asked if they were willing to be visited by the child health survey team. A random sample of those who were willing was selected and visited by these teams after the initial survey (see child health survey, below). The household module included identifiers, household assets (socio-economic status markers), education and occupation of the household head, listing of all members of the household, and location of the household using a GPS. The birth history module, for women age 13-49 years, documented live births in the previous five years, whether the child was still alive, and dates of all events. For all live births in the 1 year before the survey, further questions related to use of antenatal clinics (ANC), mosquito nets, and IPT in the most recent pregnancy, place of childbirth, attendant, and essential newborn care indicators, for the most recent birth. A series of feedback and sensitization meetings was held in Mtwara and Lindi regions in March and April 2007. The aims were (1) to sensitize the ward councillors, ward executive officers and divisional secretaries about the survey and to seek their assistance in identifying candidates for training as field interviewers, and (2) to update the list of all sub-villages (vitongoji) and obtain estimates of the numbers of households in each sub-village. Widespread support for the project team was evidenced by the assistance of local civil administrators in developing a master list of 2,766 sub-villages comprising more than 250,000 households. This list was used to plan the logistics of interviewer training and the survey itself. Two rounds of pre-piloting were done in a district adjacent to the project area in order to prepare a core team for the main survey training and to explore the feasibility of alternative approaches to the main survey, including estimates of the number of people to be interviewed per day, assessing the robustness of survey tools, development of Standard Operating Procedures for household listing, mapping and interviewing, etc. The survey tools built on experience with previous surveys in southern Tanzania which themselves had drawn heavily on standard MICS, DHS and malaria indicator surveys. The survey tools were developed into PDA-based questionnaires that were pilot tested and validated separately. The piloting activities were followed by a 1 week pre-training session for 14 facilitators. This ensured that a group of experienced interviewers was then available to support the main training, allowed further pre-testing of the PDA-based questionnaires and supported preparations for the organization of the bigger group. A total of 243 candidate interviewers took part in a three-week training and evaluation course in Mtwara in June 2007. Most of the trainees came from the study districts and had 4 years of secondary education. They were trained to seek written informed consent, list members of the household, document household assets and recent deaths in the family before completing birth histories by direct questioning of women aged 13-49 years. Specific questions were asked about related issues, such as birth preparedness and care of the newborn. These are sensitive issues for most rural women and so training aimed to prepare interviewers to ask the questions with authority, respect and understanding. Training was led by IPTi project core staff, supported by pre-trained, experienced field coordinators, and invited experts in fields such as maternal health and birth history studies. The training agenda included lectures, group discussions, field practicals and feedback sessions. During the course of training, potential team supervisors and mappers (whose job it would be to list and map all households in a sub-village) were identified and subjected to an additional training course consisting of management and quality control issues as well as field tests. Interviewers, mappers and supervisors were selected based on merit, and various techniques developed and used to assess performance during the course of training. The survey staff were split into 22 teams arranged into four platoons, each led by a Commander (a senior, experienced field supervisor). The Commander was directly in charge of five or six survey teams, each consisting of a supervisor, a mapper and seven interviewers. Each platoon had a bus and two or three four-wheel drive vehicles. The Commanders were responsible for allocating each team to a sub-village and, between them, ensuring that all sub-villages on the master list were allocated to teams according to pre-determined criteria. This ensured a balanced workload between teams and a reasonable balance of teams working in each division to minimize any potential bias. The main survey started on 25 June and lasted 128 days, finishing on 30 October. A support unit rotated between the platoons to ensure adequate supplies were maintained and to collect completed consent forms and backed-up data on CDs. These were all delivered to the project office in Mtwara where focussed data cleaning was performed before production of call lists for the child health survey team. A simple random sub-sample of eight vitongoji per division (192 of the 2,621) was chosen for the child health survey. In selected vitongoji, all households with a child under 24 months, and whose mother had agreed in principle in the main survey to be re-visited, were approached for interview approximately 2 weeks after the main survey. The child health module included questions on IPTi and vaccine coverage, breastfeeding, Vitamin A supplementation, case management and care-seeking for any recent illness. Twelve trainees were selected from the main survey group and trained from 28 June 2007 to 7 July 2007. The training comprised lectures, practical sessions, field practice on taking blood samples and interviewing, group discussions and feedback sessions. At the conclusion of training two teams of four interviewers, a driver and a supervisor started the survey itself. Call lists produced from the main survey data enabled identification of individuals for interview. Where consent was provided, mothers of all children under 2 years were interviewed. The availability of geo-coordinates from the main survey greatly enhanced the efficiency of this sub-study, which was completed on 16 November 2007. In both the main survey and the child health survey, several approaches to data quality assurance were used. Each day of the survey, for every team, these included random repeats and cross-checking of the mapping, accompanying one interview by one of the team, revisiting all households reported to be empty, and re-interviews repeating part of the questionnaire in a random sample of four interviews. Data were compared with the original interview and discrepancies discussed and resolved. Data were entered into PDAs at the time of collection, using range, logical and internal consistency checks at the time of data entry. At the end of each day a manual summary of the day's activities was produced and compared with an electronic summary of the same information. When discrepancies arose, for example as the result of incorrect entry of a cluster or household number, the source of the discrepancy was identified and recorded in a data error log sheet and in supervisors' note books. These documents were used to guide cleaning of data in Access http://www.microsoft.com. Statistical analysis was performed using STATA version 9 (College Station, Texas, USA), using an analytical plan which was reviewed by the Data and Safety Monitoring Board and agreed before the end of data collection. The primary analysis was based on a t-test of the (log) mortality rates in infants aged two-11 months in IPTi and comparison divisions, over the 2 year period between 24 May 2005 and the date of the survey visit in 2007. This approach was used, rather than individual-level regression modelling, partly because this is the recommended approach for studies with fewer than 15-20 clusters per treatment arm, and partly because there was no individual level data [11]. Restricted randomization ensured balance at baseline in infant survival, population size and district. Despite the use of restricted randomization, with only 24 clusters it was thought likely that the two groups would differ with regard to contextual factors related to infant survival, which would be potential confounders. For example, there were mosquito net campaigns in some parts of the area in 2005. As the use of treated nets is likely to be associated with better child survival, imbalances in net use would make this a potential confounder in the analysis of the effect of IPTi. Other potential confounders of the effect of IPTi, either a priori or from previous analysis, include socio-economic status, distance to the nearest health facility, maternal education, maternal age, twinning, ethnic group, and care-seeking for child illness. Baseline infant survival was also considered a potential confounder, despite the relative balance at baseline. For each of these potential confounding factors direct or proxy measures were taken from study data, using the full survey where possible as this has the largest sample size. For example, treated net use in individuals is closely related to net ownership in households, but will always be lower than household net ownership. Data on net ownership was available from all 243,612 households visited, whereas data on use of treated nets was available only in the subsample of 2,953 children included in the child health survey (between 63 and 250 from each division). Household net ownership was used as a proxy measure of treated net use in children, because of the increased sample size with this approach. Secondary analyses were planned to adjust for actual confounders from the above list. Confounding was investigated using Poisson regression analysis, and planned to adjust for any factor that changed the impact estimate by more than 15%. P-values for the adjusted impact estimate were calculated using a t-test, comparing the residuals (i.e. the ratio of observed and expected deaths) in intervention and comparison divisions from a model containing all confounders but not the effect of IPTi. Using simple graphical methods, an exploratory ecological analysis of dose-response at division level was done. The 'dose' of IPTi was estimated using division-by-division coverage of IPTi by (1) the subsample of 1,731 children aged 12-23 months from the 2007 household survey and (2) routine EPI reports from each health facility as a proxy for the dose of IPTi [A Bush et al., manuscript in preparation]. The 'response' to IPTi was estimated through the division-by-division change in mortality in infants aged two-11 months between 2001-4 and 2005-7, using the 2004 and 2007 household surveys respectively. The study was undertaken within the framework of the assessment of the community effectiveness of IPTi, part of the IPTi Consortium http://www.ipti-malaria.org. The study had ethical approval from local and national institutional review boards (Ifakara Health Institute, formerly Ifakara Health Research and Development Centre, Ifakara, and the National Tanzania Medical Research Co-coordinating Committee) through the Tanzania Commission for Science and Technology. Ethical and research clearance was also obtained from the institutional review board of the London School of Hygiene and Tropical Medicine, UK, and from the Ethics Commission of the Cantons of Basel-Stadt and Basel-Land, Switzerland. The project team in Tanzania presented the design, aims, objectives and updates of the pilot IPTi implementation project to District Councillors, who are elected representatives of the community, and benefited from their support of the intervention and its evaluation. During field work, information sheets in Swahili about the study were given out, explaining why it was being done, by whom, and what it would involve. In the household survey, written consent of all household heads was sought. In addition, women aged 13-49 years were asked to give verbal consent before the birth history interview. The trial is registered on clinical trials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT00152204","term_id":"NCT00152204"}}NCT00152204.
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