Field testing of user-friendly perennial malaria chemoprevention packaging in Benin, Côte d'Ivoire and Mozambique.

BACKGROUND: Perennial malaria chemoprevention (PMC) aims to protect children at risk from severe malaria by the administration of anti-malarial drugs to children of defined ages throughout the year. Sulfadoxine-pyrimethamine (SP) has been widely used for chemoprevention in Africa and a child-friendly dispersible tablet formulation has recently become available. METHODS: This qualitative non-interventional observational study was conducted in Benin, Côte d'Ivoire, and Mozambique between February and June 2022. Prototype blister packs, dispensing boxes and job aids designed to support dispersible SP deployment for PMC were evaluated using focus group discussions (FGD) and semi-structured in-depth individual interviews (IDI) with health authorities, health personnel, community health workers (CHWs) and caregivers. The aim was to evaluate knowledge and perceptions of malaria and chemoprevention, test understanding of the tools and identify gaps in understanding, satisfaction, user-friendliness and acceptability, and assess the potential role of CHWs in PMC implementation. Interviews were transcribed and imported to ATLAS.ti for encoding and categorization. Thematic content analysis used deductive and inductive coding with cross-referencing of findings between countries and participants to enrich data interpretation. Continuous comparison across the IDI and FGD permitted iterative, collaborative development of materials. RESULTS: Overall, 106 participants completed IDIs and 70 contributed to FGDs. Malaria was widely recognised as the most common disease affecting children, and PMC was viewed as a positive intervention to support child health. The role of CHWs was perceived differently by the target groups, with caregivers appreciating their trusted status in the community, whereas health authorities preferred clinic-based deployment of PMC by health professionals. Empirical testing of the prototype blister packs, dispensing boxes and job aids highlighted the context-specific expectations of respondents, such as familiar situations and equipment, and identified areas of confusion or low acceptance. A key finding was the need for a clear product identity reflecting malaria. CONCLUSION: Simple modifications profoundly affected the perception of PMC and influenced acceptability. Iterative quantitative investigation resulted in PMC-specific materials suited to the local context and socio-cultural norms of the target population with the aim of increasing access to chemoprevention in children most at risk of severe malaria.

Sustained clinical benefit of malaria chemoprevention with sulfadoxine-pyrimethamine (SP) in pregnant women in a region with high SP resistance markers.

OBJECTIVE: The effectiveness of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is threatened by increasing SP-resistance in Africa. We assessed the level of SP-resistance markers, and the clinical and parasitological effectiveness of IPTp-SP in southern Mozambique. METHODS: P. falciparum infection, antimalarial antibodies and dhfr/dhps SP-resistance mutants were detected by quantitative polymerase chain reaction (qPCR), suspension array technology and targeted deep sequencing, respectively, among 4016 HIV-negative women in Maputo province (2016-2019). Univariate and multivariate regression models were used to assess the association between taking the recommended three or more IPTp-SP doses (IPTp3+) and parasitological and clinical outcomes. RESULTS: 84.3% (3385/4016) women received three or more IPTp-SP doses. The prevalence of quintuple mutants at first antenatal care (ANC) visit was 94.2%. IPTp3+ was associated with a higher clearance rate of qPCR-detected infections from first ANC visit to delivery (adjusted odds ratio [aOR]=5.9, 95% CI: 1.5-33.3; p = 0.012), lower seroprevalence at delivery of antibodies against the pregnancy-specific antigen VAR2CSADBL34 (aOR=0.72, 95% CI: 0.54-0.95; p = 0.022), and lower prevalence of low birth weight deliveries (aOR: 0.61, 95% CI: 0.41-0.90; p = 0.013). CONCLUSION: A sustained parasitological effect of IPTp-SP contributes to the clinical effectiveness of IPTp3+ in areas with high prevalence of SP-resistance markers.

Predicting the effect of sulfadoxine-pyrimethamine uptake by pregnant women on birth weight using a generalized ordered partial proportional odds model.

BACKGROUND: Low birth weight is a public health problem in Africa with the cause attributable to malaria in pregnancy. World Health Organization recommends the use of intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine to prevent malaria during pregnancy. The objective of this study was to evaluate the prevalence and trajectories of birth weight and the direct impact and relationship between sulfadoxine-pyrimethamine and birth weight in Ghana since 2003. METHOD: This study used secondary data obtained from the Demographic and Health Survey conducted in Ghana since 2003. Low birth weight was defined as weight < 2500 g irrespective of the gestational age of the foetus, while normal birth weight was between 2500 g to < 4000 g and macrosomia was = > 4000 g. In all the analysis, we adjusted for clustering, stratification and weighting to reduce bias and improve precision of the estimates. Analysis was performed on each survey year as well as the pooled dataset. The generalized ordered partial proportional odds model was used due to violations of the parallel regression model assumptions. Efforts were made to identify all confounding variables and these were adjusted for. Predictive analysis was also executed. RESULTS: The overall prevalence of low birth weight was 9% while that of macrosomia was 13%. The low birth weight for 2003 was 12% while in 2008 it was 21% and then 68% in 2014. The mean birth weight of the children in 2014 was 3.16 (3.14, 3.19), 2008 was 3.37 (3.28, 3.45) and 2003 was 3.59 (3.49, 3.69) while that of the pooled data was 3.28 (3.25, 3.30). The adjusted model (taking into consideration all confounding variables) showed that non-uptake of SP could result in 51% odds of giving birth to a low-birth-weight compared with normal birth weight child. An insignificant result was observed between macrosomia and low birth weight. CONCLUSION: There is higher probability that low birth weight could increase over the next couple of years if measures are not taking to reverse the current trajectories. The uptake of sulfadoxine-pyrimethamine should continue to be encouraged and recommended because it has a direct beneficial effect on the weight of the child.

The provider's checklist to improve pregnant women coverage by intermittent preventive malaria treatment in Mali: a pilot implementation study.

BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) is a comprehensive treatment protocol of anti-malarial drugs administered to pregnant women to prevent malaria, started at the fourth pregnancy month, with at least three doses of sulfadoxine-pyrimethamine (SP), taken as directly observed treatment (DOT) every 30 days at intervals until childbirth, in combination with other preventive measures. This paper introduces feasibility and adoption concepts as implementation research outcomes (IRO), allowing after a defined intervention, to assess the coverage improvement by IPTp for women attending a reference district hospital in Mali. Specifically, the purpose is to evaluate the feasibility of a reminder tool (provider checklist) to enhance pregnant women's adoption of information about IPTp-SP uptake as immediate and sustained women practices. METHODS: The implementation strategy used a reminder checklist about malaria knowledge and the recommended preventive tools. Then, the checklist feasibility was assessed during routine practices with the adoption-level about pregnant women' knowledge. Quantitative data were collected through a questionnaire distributed to a non-probability purposive sampling targeting 200 pregnant women divided into two groups before and after the checklist intervention. In contrast, the qualitative data were based on in-depth face-to-face gynaecologists' interviews. RESULTS: Both the IROs (feasibility and adoption) were satisfactory. The gynaecologists agreed to the use of this checklist during routine practice with a recommendation to generalize it to other health providers. After a gynaecologist visit, a significant increase of the adoption-level about prior knowledge and preventive tools was noticed. A total of 83% of participants were not knowledgeable about malaria disease before checklist use versus 15% after. Similarly, coverage of women's SP DOT rose from 0 to 59% after introducing the checklist and the IPTp-SP uptake after the visit was highly significant in the second group. The latter reached 95% of pregnant women with 4-8 months' gestational age, that mostly respected all SP future visits as theoretically scheduled. CONCLUSIONS: Generalizing such a checklist reminder will improve women's knowledge about malaria prevention.

Knowledge of malaria control and attitudes towards community involvement among female community volunteers: effect of capacity building in a rural community, Southeast Nigeria.

INTRODUCTION: community volunteers have limited skills but are an important link between the community and health facilities. We determined the effect of a capacity building intervention on knowledge of malaria control and attitudes towards community involvement among female community volunteers as part of a larger community-based intervention study on pregnant women and children under five. METHODS: we conducted a before and after intervention study (no randomization or controls) among female community volunteers in Amagu community in Abakaliki Local Government Area. The intervention consisted of training sessions on knowledge of malaria and its control. The training took the form of lectures, role plays and practical demonstrations. Supportive supervision by trained community health extension workers was also provided during their field work. We compared pre-training test and post-training test scores after six months interval and analysed the data using paired t test at 5% level of significance with EPI INFO software version 7.2.3. RESULTS: the mean age of the participants was 28.5(± 6.0) years. All had a minimum level of secondary education. There was significant improvement in the mean scores of their knowledge of malaria signs and symptoms (p < 0.001), preventive measures (p < 0.001) and appropriate drug treatment (p < 0.001) in the post-training test when compared with the pre-training test. The overall mean knowledge scores pre and posttest were 147.8 and 169.8 respectively (p < 0.001) out of a maximum achievable score of 195. Also there was significant improvement in the perception of the participants on community involvement in promoting referral of pregnant women with fever (p = 0.001), the use of intermittent preventive therapy with sulphadoxine-pyrimethamine (p = 0.048) and funding initiatives to sustain activities (p = 0.037). CONCLUSION: capacity building of female community volunteers coupled with supportive supervision by trained community health workers improved the female community volunteers´ knowledge of malaria, its control and their perception of community involvement in control activities. It is recommended that the use of community volunteers as a low cost health resource can be explored further for incorporation into existing policies on malaria control in resource constrained environments.

Risk factors for Plasmodium falciparum infection in pregnant women in Burkina Faso: a community-based cross-sectional survey.

BACKGROUND: Malaria in pregnancy remains a public health problem in sub-Saharan Africa. Identifying risk factors for malaria in pregnancy could assist in developing interventions to reduce the risk of malaria in Burkina Faso and other countries in the region. METHODS: Two cross-sectional surveys were carried out to measure Plasmodium falciparum infection using microscopy in pregnant women in Saponé Health District, central Burkina Faso. Data were collected on individual, household and environmental variables and their association with P. falciparum infection assessed using multivariable analysis. RESULTS: A total of 356 pregnant women were enrolled in the surveys, 174 during the dry season and 182 during the wet season. The mean number of doses of sulfadoxine-pyrimethamine for Intermittent Preventive Treatment in pregnancy (IPTp-SP) was 0.4 doses during the first trimester, 1.1 doses at the second and 2.3 doses at the third. Overall prevalence of P. falciparum infection by microscopy was 15.7%; 17.8% in the dry season and 13.7% in the wet season. 88.2% of pregnant women reported sleeping under an insecticide-treated net (ITN) on the previous night. The odds of P. falciparum infection was 65% lower in women who reported using an ITN compared to those that did not use an ITN (Odds ratio, OR = 0.35, 95% CI 0.14-0.86, p = 0.02). IPTp-SP was also associated with reduced P. falciparum infection, with each additional dose of IPTp-SP reducing the odds of infection by 44% (OR = 0.56, 95% CI 0.39-0.79, p = 0.001). Literate women had a 2.54 times higher odds of P. falciparum infection compared to illiterate women (95% CI 1.31-4.91, p = 0.006). CONCLUSIONS: The prevalence of P. falciparum infection among pregnant women remains high in Burkina Faso, although use of IPTp-SP and ITNs were found to reduce the odds of infection. Despite this, compliance with IPTp-SP remains far from that recommended by the National Malaria Control Programme and World Health Organization. Behaviour change communication should be strengthened to encourage compliance with protective malaria control tools during pregnancy.

Effect of seasonal malaria chemoprevention plus azithromycin on Plasmodium falciparum transmission: gametocyte infectivity and mosquito fitness.

BACKGROUND: Seasonal malaria chemoprevention (SMC) consists of administration of sulfadoxine-pyrimethamine (SP) + amodiaquine (AQ) at monthly intervals to children during the malaria transmission period. Whether the addition of azithromycin (AZ) to SMC could potentiate the benefit of the intervention was tested through a double-blind, randomized, placebo-controlled trial. The effect of SMC and the addition of AZ, on malaria transmission and on the life history traits of Anopheles gambiae mosquitoes have been investigated. METHODS: The study included 438 children randomly selected from among participants in the SMC + AZ trial and 198 children from the same area who did not receive chemoprevention. For each participant in the SMC + AZ trial, blood was collected 14 to 21 days post treatment, examined for the presence of malaria sexual and asexual stages and provided as a blood meal to An. gambiae females using a direct membrane-feeding assay. RESULTS: The SMC treatment, with or without AZ, significantly reduced the prevalence of asexual Plasmodium falciparum (LRT X22 = 69, P < 0.0001) and the gametocyte prevalence (LRT X22 = 54, P < 0.0001). In addition, the proportion of infectious feeds (LRT X22 = 61, P < 0.0001) and the prevalence of oocysts among exposed mosquitoes (LRT X22 = 22.8, P < 0.001) was reduced when mosquitoes were fed on blood from treated children compared to untreated controls. The addition of AZ to SPAQ was associated with an increased proportion of infectious feeds (LRT X21 = 5.2, P = 0.02), suggesting a significant effect of AZ on gametocyte infectivity. There was a slight negative effect of SPAQ and SPAQ + AZ on mosquito survival compared to mosquitoes fed with blood from control children (LRTX22 = 330, P < 0.0001). CONCLUSION: This study demonstrates that SMC may contribute to a reduction in human to mosquito transmission of P. falciparum, and the reduced mosquito longevity observed for females fed on treated blood may increase the benefit of this intervention in control of malaria. The addition of AZ to SPAQ in SMC appeared to enhance the infectivity of gametocytes providing further evidence that this combination is not an appropriate intervention.

Decomposition of socioeconomic inequalities in the uptake of intermittent preventive treatment of malaria in pregnancy in Nigeria: evidence from Demographic Health Survey.

BACKGROUND: Although malaria in pregnancy is preventable with the use of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP), it still causes maternal morbidity and mortality, in sub-Saharan Africa and Nigeria in particular. Socioeconomic inequality leads to limited uptake of IPTp-SP by pregnant women and is, therefore, a public health challenge in Nigeria. This study aimed to measure and identify factors explaining socioeconomic inequality in the uptake of IPTp-SP in Nigeria. METHODS: The study re-analysed dataset of 12,294 women aged 15-49 years from 2018 Nigeria Demographic Health Survey (DHS). The normalized concentration index (Cn) and concentration curve were used to quantify and graphically present socioeconomic inequalities in the uptake of IPTp-SP among pregnant women in Nigeria. The Cn was decomposed to identify key factors contributing to the observed socioeconomic inequality in the uptake of adequate (≥ 3) IPTp-SP. RESULTS: The study showed a higher concentration of the adequate uptake of IPTp-SP among socioeconomically advantaged women (Cn = 0.062; 95% confidence interval [CI] 0.048 to 0.076) in Nigeria. There is a pro-rich inequality in the uptake of IPTp-SP in urban areas (Cn = 0.283; 95%CI 0.279 to 0.288). In contrast, a pro-poor inequality in the uptake of IPTp-SP was observed in rural areas (Cn = - 0.238; 95%CI - 0.242 to - 0.235). The result of the decomposition analysis indicated that geographic zone of residence and antenatal visits were the two main drivers for the concentration of the uptake of IPTp-SP among wealthier pregnant women in Nigeria. CONCLUSION: The pro-rich inequalities in the uptake of IPTp-SP among pregnant women in Nigeria, particularly in urban areas, warrant further attention. Strategies to improve the uptake of IPTp-SP among women residing in socioeconomically disadvantaged geographic zones (North-East and North-West) and improving antenatal visits among the poor women may reduce pro-rich inequality in the uptake of IPTp-SP among pregnant women in Nigeria.

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs.

BACKGROUND: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. DATA SOURCES: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Predictors for the uptake of optimal doses of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy in Tanzania: further analysis of the data of the 2015-2016 Tanzania demographic and health survey and malaria indicator survey.

BACKGROUND: In Tanzania, the uptake of optimal doses (≥ 3) of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria (IPTp-SP) during pregnancy has remained below the recommended target of 80%. Therefore, this study aimed to investigate the predictors for the uptake of optimal IPTp-SP among pregnant women in Tanzania. METHODS: This study used data from the 2015-16 Tanzania demographic and health survey and malaria indicator survey (TDHS-MIS). The study had a total of 4111 women aged 15 to 49 who had live births 2 years preceding the survey. The outcome variable was uptake of three or more doses of IPTp-SP, and the independent variables were age, marital status, education level, place of residence, wealth index, occupation, geographic zone, parity, the timing of first antenatal care (ANC), number of ANC visits and type of the health facility for ANC visits. Predictors for the optimal uptake of IPTp-SP were assessed using univariate and multivariable logistic regression. RESULTS: A total of 327 (8%) women had optimal uptake of IPTp-SP doses. Among the assessed predictors, the following were significantly associated with optimal uptake of IPTp-SP doses; education level [primary (AOR: 2.2, 95% CI 1.26-3.67); secondary or higher education (AOR: 2.1, 95% CI 1.08-4.22)], attended ANC at the first trimester (AOR: 2.4, 95% CI 1.20-4.96), attended ≥ 4 ANC visits (AOR: 1.9, 95% CI 1.34-2.83), attended government health facilities (AOR: 1.5, 95% CI 1.07-1.97) and geographic zone [Central (AOR: 5, 95% CI 2.08-11.95); Southern Highlands (AOR: 2.8, 95% CI 1.15-7.02); Southwest Highlands (AOR: 2.7, 95% CI 1.03-7.29); Lake (AOR: 3.5, 95% CI 1.51-8.14); Eastern (AOR: 1.5, 95% CI 1.88-11.07)]. CONCLUSIONS: The uptake of optimal IPTp-SP doses is still low in Tanzania. The optimal uptake of IPTp-SP was associated with attending ANC in the first trimester, attending more than four ANC visits, attending government health facility for ANC, having primary, secondary, or higher education level, and geographic zone. Therefore, there is a need for health education and behavior change interventions with an emphasis on the optimal use of IPTp-SP doses.

Suboptimal Intermittent Preventive Treatment in Pregnancy (IPTp) is Associated With an Increased Risk of Submicroscopic Plasmodium falciparum Infection in Pregnant Women: A Prospective Cohort Study in Benin.

BACKGROUND: Harmful maternal and neonatal health outcomes result from malaria in pregnancy, the prevention of which primarily relies on intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). The World Health Organization recommends IPTp-SP in sub-Saharan Africa, but implementation is highly heterogeneous and often suboptimal in terms of the number of doses and their timing. In this study, we assessed the impact of this heterogeneity on malaria in pregnancy, mainly with respect to submicroscopic Plasmodium falciparum infections. METHODS: We used data from 273 Beninese women followed throughout pregnancy. Screening for P. falciparum infections, using both microscopy-based and polymerase chain reaction (PCR)-based methods, was performed monthly, and information on IPTp-SP doses was collected. Gestational age was estimated by repeated ultrasound scans. Using a negative binomial model, we investigated the effect of IPTp-SP doses and timing after 17 weeks of gestation on the number of P. falciparum infections, focusing on submicroscopic infections detectable only by PCR. RESULTS: At least 2 IPTp-SP doses were taken by 77.3% of the women. The median gestational age at the first IPTp-SP dose was 22 weeks. A late first IPTp-SP dose (>21.2 weeks) was marginally associated with an increased number of P. falciparum infections (adjusted incidence rate ratio [aIRR] = 1.3; P = .098). The number of IPTp-SP doses was not associated with the number of submicroscopic infections (aIRR = 1.2, P = .543). CONCLUSIONS: A late first IPTp-SP dose failed to provide optimal protection against P. falciparum, especially submicroscopic infections. This highlights the need for a new antimalarial drug for IPTp that could be taken early in pregnancy.

Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein-Mediated Drug-Drug Interactions in Healthy Volunteers.

Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1 -methylnicotinamide (1-NMN)), N1 -methyladenosine (m1 A) was included as novel biomarkers. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well-correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.

Infant sex modifies associations between placental malaria and risk of malaria in infancy.

BACKGROUND: Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. METHODS: Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0-20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. RESULTS: There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. CONCLUSION: PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622.

Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) aims to prevent malaria in children during the high malaria transmission season. The Achieving Catalytic Expansion of SMC in the Sahel (ACCESS-SMC) project sought to remove barriers to the scale-up of SMC in seven countries in 2015 and 2016. We evaluated the project, including coverage, effectiveness of the intervention, safety, feasibility, drug resistance, and cost-effectiveness. METHODS: For this observational study, we collected data on the delivery, effectiveness, safety, influence on drug resistance, costs of delivery, impact on malaria incidence and mortality, and cost-effectiveness of SMC, during its administration for 4 months each year (2015 and 2016) to children younger than 5 years, in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger, and Nigeria. SMC was administered monthly by community health workers who visited door-to-door. Drug administration was monitored via tally sheets and via household cluster-sample coverage surveys. Pharmacovigilance was based on targeted spontaneous reporting and monitoring systems were strengthened. Molecular markers of resistance to sulfadoxine-pyrimethamine and amodiaquine in the general population before and 2 years after SMC introduction was assessed from community surveys. Effectiveness of monthly SMC treatments was measured in case-control studies that compared receipt of SMC between patients with confirmed malaria and neighbourhood-matched community controls eligible to receive SMC. Impact on incidence and mortality was assessed from confirmed outpatient cases, hospital admissions, and deaths associated with malaria, as reported in national health management information systems in Burkina Faso and The Gambia, and from data from selected outpatient facilities (all countries). Provider costs of SMC were estimated from financial costs, costs of health-care staff time, and volunteer opportunity costs, and cost-effectiveness ratios were calculated as the total cost of SMC in each country divided by the predicted number of cases averted. FINDINGS: 12 467 933 monthly SMC treatments were administered in 2015 to a target population of 3 650 455 children, and 25 117 480 were administered in 2016 to a target population of 7 551 491. In 2015, among eligible children, mean coverage per month was 76·4% (95% CI 74·0-78·8), and 54·5% children (95% CI 50·4-58·7) received all four treatments. Similar coverage was achieved in 2016 (74·8% [72·2-77·3] treated per month and 53·0% [48·5-57·4] treated four times). In 779 individual case safety reports over 2015-16, 36 serious adverse drug reactions were reported (one child with rash, two with fever, 31 with gastrointestinal disorders, one with extrapyramidal syndrome, and one with Quincke's oedema). No cases of severe skin reactions (Stevens-Johnson or Lyell syndrome) were reported. SMC treatment was associated with a protective effectiveness of 88·2% (95% CI 78·7-93·4) over 28 days in case-control studies (2185 cases of confirmed malaria and 4370 controls). In Burkina Faso and The Gambia, implementation of SMC was associated with reductions in the number of malaria deaths in hospital during the high transmission period, of 42·4% (95% CI 5·9 to 64·7) in Burkina Faso and 56·6% (28·9 to 73·5) in The Gambia. Over 2015-16, the estimated reduction in confirmed malaria cases at outpatient clinics during the high transmission period in the seven countries ranged from 25·5% (95% CI 6·1 to 40·9) in Nigeria to 55·2% (42·0 to 65·3) in The Gambia. Molecular markers of resistance occurred at low frequencies. In individuals aged 10-30 years without SMC, the combined mutations associated with resistance to amodiaquine (pfcrt CVIET haplotype and pfmdr1 mutations [86Tyr and 184Tyr]) had a prevalence of 0·7% (95% CI 0·4-1·2) in 2016 and 0·4% (0·1-0·8) in 2018 (prevalence ratio 0·5 [95% CI 0·2-1·2]), and the quintuple mutation associated with resistance to sulfadoxine-pyrimethamine (triple mutation in pfdhfr and pfdhps mutations [437Gly and 540Glu]) had a prevalence of 0·2% (0·1-0·5) in 2016 and 1·0% (0·6-1·6) in 2018 (prevalence ratio 4·8 [1·7-13·7]). The weighted average economic cost of administering four monthly SMC treatments was US$3·63 per child. INTERPRETATION: SMC at scale was effective in preventing morbidity and mortality from malaria. Serious adverse reactions were rarely reported. Coverage varied, with some areas consistently achieving high levels via door-to-door campaigns. Markers of resistance to sulfadoxine-pyrimethamine and amodiaquine remained uncommon, but with some selection for resistance to sulfadoxine-pyrimethamine, and the situation needs to be carefully monitored. These findings should support efforts to ensure high levels of SMC coverage in west and central Africa. FUNDING: Unitaid.

Reaching the unreached: effectiveness and satisfaction with community-directed distribution of sulfadoxine-pyrimethamine for preventing malaria in pregnancy in rural South-East, Nigeria.

BACKGROUND: Innovative community strategies to increase intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) coverage is advocated particularly in rural areas, where health infrastructure is weakest and malaria transmission highest. This study involved proof-of-concept implementation research to determine satisfaction with and effectiveness of community-directed distribution of IPTp-SP on uptake among pregnant women in Ebonyi State, Nigeria. METHODS: This before-and-after study was carried out in 2019 in a rural community in Ebonyi State Nigeria. The intervention involved advocacy visits, community-wide sensitizations on malaria prevention, house-to-house directly observed IPTp-SP administration, and follow-up visits by trained community-selected community-directed distributors (CDDs). Monthly IPTp-SP coverage was assessed over 5 months and data analysed using SPSS version 20. RESULTS: During the study, 229 women received the first dose of IPTp while 60 pregnant women received 5 or more doses of IPTp. The uptake of ≥ 3 IPTp doses increased from 31.4% before the community-directed distribution of IPTp to 71.6% (P < 0.001) by the fourth month post-initiation of the community-directed distribution of IPTp. Sleeping under insecticide-treated net (ITN) the night before the survey increased from 62.4 to 84.3% (P < 0.001) while reporting of fever during pregnancy decreased from 64.9 to 17.0% (P < 0.001). Although antenatal clinic utilization increased in the primary health centre serving the community, traditional birth attendants and patent medicine vendors in the community remained more patronized. Post-intervention, most mothers rated CDD services well (93.6%), were satisfied (97.6%), and preferred community IPTp administration to facility administration (92.3%). CONCLUSION: Community-directed distribution of IPTp-SP improved uptake of IPTp-SP and ITN use. Mothers were satisfied with the services. The authors recommend sustained large-scale implementation of community-directed distribution of IPTp with active community engagement.

Inequities in the use of sulphadoxine-pyrimethamine for malaria prophylaxis during pregnancy in Nigeria.

Background: Intermittent presumptive treatment in pregnancy (IPTp) of malaria using sulfadoxine-pyrimethamine (SP) was introduced in Nigeria in 2005 to reduce the burden of malaria in pregnancy. By 2013, 23% of reproductive aged women surveyed received SP for malaria prevention in their last pregnancy of the past 5 years. This paper highlights geographic and socio-economic variations and inequities in accessing and using SP for malaria prophylaxis in pregnancy in Nigeria, as well as client-related and service delivery determinants. Methods: Secondary data from 2013 Nigeria demographic and health survey (DHS) was used. Sample of 38,948 eligible women were selected for interview using stratified three-stage cluster design. Data obtained from the individual recode dataset was used for descriptive and logistic regression analysis of factors associated with SP use in pregnancy was performed. Independent variables were age, media exposure, region, place of residence, wealth index, place of antenatal care (ANC) attendance and number of visits. Results: Women in the upper three wealth quintiles were 1.33 - 1.80 times more likely to receive SP than the poorest (CI: 1.15-1.56; 1.41-1.97; 1.49-2.17). Women who received ANC from public health facilities were twice as likely (inverse of OR 0.68) to use SP in pregnancy than those who used private facilities (CI: 0.60-0.76). Those who attended at least 4 ANC visits were 1.46 times more likely to get SP prophylaxis (CI: 1.31-1.63). Using the unadjusted odds ratio, women residing in rural areas were 0.86 times less likely to use SP compared to those in urban areas. Conclusions: Inequities in access to and use of SP for malaria prophylaxis in pregnancy exist across sub-population groups in Nigeria. Targeted interventions on the least covered are needed to reduce existing inequities and scale-up IPTp of malaria.

A cluster randomized trial of delivery of intermittent preventive treatment of malaria in pregnancy at the community level in Burkina Faso.

BACKGROUND: Malaria in pregnancy is responsible for 8-14% of low birth weight and 20% of stillbirths in sub-Saharan Africa. To prevent these adverse consequences, the World Health Organization recommends intermittent preventive treatment of pregnant women (IPTp) with sulfadoxine-pyrimethamine be administered at each ANC visit starting as early as possible in the second trimester. Global IPTp coverage in targeted countries remains unacceptably low. Community delivery of IPTp was explored as a means to improve coverage. METHODS: A cluster randomized, controlled trial was conducted in 12 health facilities in a 1:1 ratio to either an intervention group (IPTp delivered by CHWs) or a control group (standard practice, with IPTp delivered at HFs) in three districts of Burkina Faso to assess the effect of IPTp administration by community health workers (CHWs) on the coverage of IPTp and antenatal care (ANC). The districts and facilities were purposively selected taking into account malaria epidemiology, IPTp coverage, and the presence of active CHWs. Pre- and post-intervention surveys were carried out in March 2017 and July-August 2018, respectively. A difference in differences (DiD) analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level. RESULTS: Altogether 374 and 360 women were included in the baseline and endline surveys, respectively. At baseline, women received a median of 2.1 doses; by endline, women received a median of 1.8 doses in the control group and 2.8 doses in the intervention group (p-value < 0.0001). There was a non-statistically significant increase in the proportion of women attending four ANC visits in the intervention compared to control group (DiD = 12.6%, p-value = 0.16). By the endline, administration of IPTp was higher in the intervention than control, with a DiD of 17.6% for IPTp3 (95% confidence interval (CI) - 16.3, 51.5; p-value 0.31) and 20.0% for IPTp4 (95% CI - 7.2, 47.3; p-value = 0.15). CONCLUSIONS: Community delivery of IPTp could potentially lead to a greater number of IPTp doses delivered, with no apparent decrease in ANC coverage.

Factors associated with the uptake of intermittent preventive treatment of malaria in pregnancy in the Bamenda health districts, Cameroon.

INTRODUCTION: The World Health Organization (WHO) recommends that in malaria endemic areas with moderate to high transmission rates, pregnant women presenting for antenatal clinic (ANC) should receive at least three doses of intermittent preventive treatment in pregnancy (IPTp) for malaria between the 16th and 36th weeks of pregnancy at intervals of 4 weeks between doses. Several challenges remain in effective implementation of IPTp policy making the targeted coverage (80%) of the third doses of IPTp far from being achieved. The main objective of this study was to assess factors associated with the uptake of IPTp among pregnant women attending ANCs in the Bamenda Health District. METHODS: To reach our objectives, we carried out a cross-sectional study following informed consent with thirty-nine (39) healthcare workers (HCW) and four hundred (400) pregnant women who were either in the third trimester of pregnancy or had recently given birth in any of thirty-six (36) health facilities (HF) within the Bamenda Health District (BHD) from May to August 2014. All sites within the BHD were included. The participants were selected by simple random sampling. The principal research instrument was a structured and pre-tested questionnaire that was designed to capture socio-demographic data and data related to stage of pregnancy and knowledge about IPTp. Data was entered using Ms Excel and analysed using SPSS v20.0. Descriptive statistics (frequencies and percentages) was used to report findings. We used Chi-Square test to compare the categorical variables (Fischer's exact test was used in cases were conditions for Chi-Square test were not met). RESULTS: Uptake for at least one dose of IPTp was 95.3% (381/400) and 54.9% (209/400) had received all three doses, 15.5% (59/400) received only one dose and 4.8% (19/400) did not receive any of the doses of IPTp. Knowledge about IPTp was associated with an increase uptake of IPTp (P<0.001). All health care providers were knowledgeable about the importance and use of IPTp. However, 35.9% reported not receiving any training on IPTp. Among the health providers, 28.2% did not know when to start IPTp and 43.59% did not know when to stop IPTp. Out of all the health care providers, 30.77% complained of medication (sulfadoxine-Pyrimethamine) stock out and 84.62% practiced the policy of direct observed therapy. CONCLUSION: The uptake of the third dose of IPTp is poor in the Bamenda Health District and this may be attributed to medication stock out and inadequacy of routine trainings for the health providers. The good practice observed was that of direct observed therapy by HCWs. Patient knowledge about IPTp in our study was associated with better uptake of IPTp. Encouraging education of pregnant women on the importance of IPTp, providing routine training to HCWs and promoting direct observation of therapy may improve on IPTp uptake during pregnancy.

Correlates of uptake of optimal doses of sulfadoxine-pyrimethamine for prevention of malaria during pregnancy in East-Central Uganda.

BACKGROUND: In 2012, the World Health Organization recommended that pregnant women in malaria-endemic countries complete at least three (optimal) doses of intermittent preventive treatment (IPTp) using sulfadoxine-pyrimethamine (SP) to prevent malaria and related adverse events during pregnancy. Uganda adopted this recommendation, but uptake remains low in East-Central and information to explain this low uptake remains scanty. This analysis determined correlates of uptake of optimal doses of IPTp-SP in East-Central Uganda. METHODS: This was a secondary analysis of the 2016 Uganda Demographic Health Survey data on 579 women (15-49 years) who attended at least one antenatal care (ANC) visit and had a live birth within 2 years preceding the survey. Uptake of IPTp-SP was defined as optimal if a woman received at least three doses; partial if they received 1-2 doses or none if they received no dose. Multivariate analysis using multinomial logistic regression was used to determine correlates of IPTp-SP uptake. RESULTS: Overall, 22.3% of women received optimal doses of IPTp-SP, 48.2% partial and 29.5% none. Attending ANC at a lower-level health centre relative to a hospital was associated with reduced likelihood of receiving optimal doses of IPTp-SP. Belonging to other religious faiths relative to Catholic, belonging to a household in the middle relative to poorest wealth index, and age 30 and above years relative to 25-29 years were associated with higher likelihood of receiving optimal doses of IPTp-SP. CONCLUSIONS: In East-Central Uganda, uptake of optimal doses of IPTp-SP is very low. Improving institutional delivery and household wealth, involving religious leaders in programmes to improve uptake of IPTp-SP, and strengthening IPTp-SP activities at lower level health centers may improve uptake of IPTp-SP in the East-Central Uganda.