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Background. Intermittent preventive treatment with sulphadoxine- pyrimethamine (IPTp-SP) is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW) and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome. Methods. Pregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2) or 3 doses (SP3) of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW (<2500 g), severe anaemia (Hb < 8 g/dL) and premature birth was analysed using intention-to-treat (ITT) and per-protocol (PP) analysis. Results. Data from 1274 singleton pregnancies were analysed (641 in the SP3 and 633 in the SP2 group). The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24) in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 – 0.90). The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance. Conclusion. The risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal. © 2010 Valea et al; licensee BioMed Central Ltd.
The study was conducted between March 2006 and July 2008 in two peripheral health centres (Koho and Karaba) located in Houndé health district. Houndé is situated at about 100 km from Bobo-Dioulasso, in west Burkina Faso. Malaria is holo-endemic with marked seasonal (June – December) transmission [19]. The district hospital and the 28 peripheral health facilities located in its catchment area cover a population of approximately 247,500 people [20]. In 2007, it was estimated that about 12,500 pregnant women were at risk of malaria. Malaria represented 38% of all consultations and 52% of hospitalizations in the health district. Attendance rates to the 2nd ANC visit was estimated at 69.6%. Only 25.2% pregnant women attended the ANC before the second trimester of pregnancy. The prevalence of LBW among deliveries in health facilities was estimated at 16.0%, one of the highest figures in Burkina Faso [20]. Before its implementation as IPTp, SP resistance was low in Burkina Faso, with the PCR-adjusted treatment failure at day 28 among children 6 months-15 years of age estimated at 8.2% [21]. This study was part of a larger one investigating the impact of a fortified food supplement (FFS) versus multiple micronutrients supplement (MMS) on pregnancy outcome [22]. Pregnant women were randomized using a factorial design in permuted blocks of four to receive either: (1) two-dose SP + FFS, (2) two-dose SP + MMS, (3) three-dose SP + FSS or (4) three-dose SP + MMS. Therefore, for malaria participants were assigned to receive either the two-dose SP (SP2 group) as recommended by the National Malaria Control Program (NMCP) in Burkina Faso, or the three-dose SP (SP3 group) regimen. Randomization numbers generated by a computer programme were printed and sealed in individual opaque envelopes that were opened only when the study physician identified an eligible subject. Drug administrations were scheduled by a field pharmacist according to the gestational age at randomization and given at home by the field workers. Nutritional supplementation consisted of a daily administration of MMS or FFS as described elsewhere [22]. The sample size was estimated on the proportion of LBW as the primary outcome. Assuming the prevalence of LBW in the control group (SP2) at 15% and a loss to follow up around 10%, 542 participants per arm should be able to show a 40% reduction (from 15% to 9%) in LBW at 80% power and 5% significance. The study participants were recruited through a community-based network of 30 field workers, as described by Huybregts et al [22]. Briefly, during a census, all women of childbearing age in the study area were identified and registered. Monthly visits by trained field workers were carried out over the whole study area to screen for pregnant cases. When pregnancy was suspected, participants were referred to one of the two health facilities for a formal pregnancy test. Written informed consent was obtained from those agreeing to participate to the study after explaining the study purpose and procedures. Women with known hypersensitivity to SP or not planning to stay in the study area for the following two years were excluded. The study protocol was approved by the Ethical Committees of the Centre Muraz, Bobo-Dioulasso, Burkina Faso, and the Institute of Tropical Medicine, Antwerp, Belgium. The study was registered at http://ClinicalTrial.gov registry (identifier: {"type":"clinical-trial","attrs":{"text":"NCT00909974","term_id":"NCT00909974"}}NCT00909974). Women were enrolled at the first ANC visit. Demographic data and medical and pregnancy history were recorded. Clinical examination was performed and vital signs, weight, height and arm circumference were recorded. These measures were repeated at each ANC visit. Gestational age was assessed by an obstetrician by performing a trans-abdominal ultrasound foetal biometry. The field workers visited the women at home for the drug administration according to the predefined drug delivery schedule. All women received the first IPTp-SP dose at the beginning of the second trimester of pregnancy, after quickening, and the second one at the beginning of the third trimester as recommended by the NMCP. In addition, women in the SP3 group received a third IPTp-SP dose one month after the second dose if this one occurred before 34 weeks of gestation. If not, the administration of the third dose was cancelled. Women identified during the first trimester of pregnancy did not receive any anti-malarial treatment before the second trimester of pregnancy unless they had clinical malaria defined by a positive slide at any parasite density together with fever. If so, they were referred to the health facilities to receive an appropriate care. Women were paid home visits daily by the field workers who collected information about any complaint after their previous visit and recorded body temperature. In case of fever (body temperature ≥37.5°C) or history of fever since the last visit, a blood sample for parasitaemia (thick and thin blood film) and later genotyping (on filter paper) was collected. Women with malaria infection were treated with a full course of quinine (24 mg/kg/day for 7 days). Pregnant women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed and measured twice by two different members of the health staff. Duplicate thick and thin blood smears were collected at different time points, i.e. at the first ANC visit, before SP administration, whenever a malaria infection was suspected and at delivery. Slides were stained with Giemsa 10% (pH 7.2) and parasites were counted against 200 WBC. Ten percent of the slides were randomly selected and sent to the Centre Muraz for quality control. Maternal haemoglobin (Hb) was measured by Hemocue (HemoCue Ltd, UK) at the first and the third ANC visits. Primary outcome was LBW prevalence. Secondary outcomes were the occurrence of anaemia, miscarriage, prematurity, stillbirth and neonatal mortality. LBW was defined as birth weight < 2500 g. Anaemia and severe anaemia were defined as Hb < 11 g/dL and Hb < 8 g/dL, respectively. Miscarriage was defined as delivery before 28 weeks of gestation; prematurity as ≤37 weeks of gestation, according to the gestational age at enrolment as given by the ultrasound biometry; stillbirth as delivery of a dead baby after 28 weeks of gestation; neonatal death as death within the first 28 days of life. Adolescents were defined as women ≤ 19 years old. Malaria infection was defined as detection by microscopy of Plasmodium falciparum asexual stages, any density. Explanatory variables and possible confounders included the study arm, the number of SP doses received (1, 2 or 3), parity (3 groups: primigravidae, gravidae 2-3, gravidae ≥4), body mass index at enrolment, malaria infection, malaria transmission season at delivery (low transmission season from January to May and high transmission season from June to December) and the nutritional supplement group women belonged to. Data were double entered in a Microsoft Access® database. Validation and analysis were performed using Stata/IC® version 10.0 software. Only singleton pregnancies were included in the analysis. Intention-to-treat (ITT) and a per-protocol (PP) analysis were performed. Since a substantial proportion of women in the SP3 group did not received the third dose of SP, an additional individual efficacy (IE) analysis was carried out. The ITT analysis included all randomized patients for whom the outcome variables were available and the effect of the intervention was determined by comparing the SP2 group to the SP3 group, regardless of the actual number of IPTp-SP doses received by the women. The PP analysis included women randomized in the SP3 group who actually received three doses and women randomized in the SP2 group who received two doses of SP and for whom the outcomes data were available. The IE analysis divided women in groups according to the number of IPTp-SP doses actually received (one, two or three), regardless of the randomization group they belonged to. Comparison of mean values of continuous variables was done by analysis of variance, while for categorical variables a Poisson regression model with robust standard error estimates was used to evaluate the relationship between explanatory variables and outcomes. Parity, maternal age, corrected weight status at inclusion (underweight: body mass index <18.5 kg/m2; or normal weight) malaria infection and malaria transmission season at delivery were included in the model as possible confounders. A p-value ≤ 0.05 was considered as statistically significant.
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