Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV. METHODS: We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713. FINDINGS: From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups. INTERPRETATION: Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy. FUNDING: European and Developing Countries Clinical Trials Partnership 2; UK Joint Global Health Trials Scheme (UK Foreign, Commonwealth and Development Office; Medical Research Council; National Institute for Health Research; Wellcome); and Swedish International Development Cooperation Agency.

Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.

Expanding community case management of malaria to all ages can improve universal access to malaria diagnosis and treatment: results from a cluster randomized trial in Madagascar.

BACKGROUND: Global progress on malaria control has stalled recently, partly due to challenges in universal access to malaria diagnosis and treatment. Community health workers (CHWs) can play a key role in improving access to malaria care for children under 5 years (CU5), but national policies rarely permit them to treat older individuals. We conducted a two-arm cluster randomized trial in rural Madagascar to assess the impact of expanding malaria community case management (mCCM) to all ages on health care access and use. METHODS: Thirty health centers and their associated CHWs in Farafangana District were randomized 1:1 to mCCM for all ages (intervention) or mCCM for CU5 only (control). Both arms were supported with CHW trainings on malaria case management, community sensitization on free malaria care, monthly supervision of CHWs, and reinforcement of the malaria supply chain. Cross-sectional household surveys in approximately 1600 households were conducted at baseline (Nov-Dec 2019) and endline (Nov-Dec 2021). Monthly data were collected from health center and CHW registers for 36 months (2019-2021). Intervention impact was assessed via difference-in-differences analyses for survey data and interrupted time-series analyses for health system data. RESULTS: Rates of care-seeking for fever and malaria diagnosis nearly tripled in both arms (from less than 25% to over 60%), driven mostly by increases in CHW care. Age-expanded mCCM yielded additional improvements for individuals over 5 years in the intervention arm (rate ratio for RDTs done in 6-13-year-olds, RRRDT6-13 years = 1.65; 95% CIs 1.45-1.87), but increases were significant only in health system data analyses. Age-expanded mCCM was associated with larger increases for populations living further from health centers (RRRDT6-13 years = 1.21 per km; 95% CIs 1.19-1.23). CONCLUSIONS: Expanding mCCM to all ages can improve universal access to malaria diagnosis and treatment. In addition, strengthening supply chain systems can achieve significant improvements even in the absence of age-expanded mCCM. TRIAL REGISTRATION: The trial was registered at the Pan-African Clinical Trials Registry (#PACTR202001907367187).

WHO antenatal care policy and prevention of malaria in pregnancy in sub-Saharan Africa.

BACKGROUND: The WHO 2016 antenatal care (ANC) policy recommends at least eight antenatal contacts during pregnancy. This study assessed ANC8 uptake following policy implementation and explored the relationship between ANC attendance and intermittent preventive treatment in pregnancy (IPTp) coverage in sub-Saharan Africa following the rollout of the World Health Organization (WHO) 2016 ANC policy, specifically, to assess differences in IPTp uptake between women attending eight versus four ANC contacts. METHODS: A secondary analysis of data from 20 sub-Saharan African countries with available Demographic Health and Malaria Indicator surveys from 2018 to 2023 was performed. The key variables were the number of ANC contacts and IPTp doses received during a participant's last completed pregnancy in the past two years. Pooled crude and multivariable logistic regression models were used to explore factors associated with attendance of at least four or eight ANC contacts as well as receipt of at least three doses of IPTp during pregnancy. RESULTS: Overall, only a small proportion of women (median = 3.9%) completed eight or more ANC contacts (ANC8 +). Factors significantly associated with increased odds of ANC8 + included early ANC attendance (AOR: 4.61: 95% CI 4.30-4.95), literacy (AOR: 1.20; 95% CI 1.11-1.29), and higher wealth quintile (AOR: 3.03; 95% CI 2.67-3.44). The pooled estimate across all countries showed a very slight increase in the odds of IPTp3 + among women with eight (AOR: 1.06; 95% CI 1.00-1.12) compared to those with four contacts. In all but two countries, having eight instead of four ANC contacts did not confer significantly greater odds of receiving three or more doses of IPTp (IPTp3 +), except in Ghana (AOR: 1.67; 95% CI 1.38-2.04) and Liberia (AOR: 1.43; 95% CI 1.18-1.72). CONCLUSION: Eight years after the WHO ANC policy recommendation, all countries still had sub-optimal ANC8 + coverage rates. This paper is a call to action to actualize the vision of the WHO and the global malaria community of a malaria free world. Policies to improve ANC and IPTp coverage should be operationalized with clear actionable guidance and local ownership. Study findings can be used to inform multi-level policy, programmatic, and research recommendations to optimize ANC attendance and malaria in pregnancy prevention, thus improving maternal and child health outcomes, including the reduction of malaria in pregnancy.

Effectiveness of Intermittent Screening and Treatment of Malaria in Pregnancy on Maternal and Birth Outcomes in Selected Districts in Rwanda: A Cluster Randomized Controlled Trial.

BACKGROUND: Malaria during pregnancy can cause serious consequences including maternal anemia and low birthweight (LBW). Routine antenatal care (ANC) in Rwanda includes malaria symptom screening at each ANC visit. This cluster randomized controlled trial investigated whether adding intermittent screening with a malaria rapid diagnostic test at each routine ANC visit and treatment of positives during pregnancy (ISTp) is more effective than routine ANC for reducing malaria prevalence at delivery. METHODS: Between September 2016 and June 2018, pregnant women initiating ANC at 14 health centers in Rwanda were enrolled into ISTp or control arms. All women received an insecticide-treated bed net at enrollment. Hemoglobin concentration, placental and peripheral parasitemia, newborn outcome, birthweight, and prematurity were assessed at delivery. RESULTS: Nine hundred seventy-five women were enrolled in ISTp and 811 in the control group. Routine ANC plus ISTp did not significantly reduce polymerase chain reaction-confirmed placental malaria compared to control (adjusted relative risk [aRR], 0.94 [95% confidence interval {CI}, .59-1.50]; P = .799). ISTp had no impact on anemia (aRR, 1.08 [95% CI, .57-2.04]; P = .821). The mean birthweight of singleton newborns was not significantly different between arms (3054 g vs 3096 g, P = .395); however, women in the ISTp arm had a higher proportion of LBW (aRR, 1.59 [95% CI, 1.02-2.49]; P = .042). CONCLUSIONS: This is the only study to compare ISTp to symptomatic screening at ANC in a setting where intermittent preventive treatment is not routinely provided. ISTp did not reduce the prevalence of malaria or anemia at delivery and was associated with an increased risk of LBW. CLINICAL TRIALS REGISTRATION: NCT03508349.

Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya.

BACKGROUND: Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot. METHODS: From March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests. RESULTS: Of 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters. CONCLUSIONS: Knowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

Perceptions and drivers of healthcare provider and drug dispenser practices for the treatment of malaria in pregnancy in the context of multiple first-line therapies in western Kenya: a qualitative study.

BACKGROUND: Emergence of Plasmodium falciparum resistance to artemether-lumefantrine in Africa prompted the pilot introduction of multiple first-line therapies (MFT) against malaria in Kenya, potentially exposing women-of-childbearing-age (WOCBAs) to anti-malarials with unknown safety profiles in the first trimester. This qualitative study explored knowledge and perceptions among healthcare providers providing malaria treatment to WOCBAs and pregnant women. METHODS: In-depth interviews were conducted with purposively selected public and private health facility (HF) and drug outlet (DO) providers within and outside the pilot-MFT area. County health managers were interviewed about their knowledge of the national treatment guidelines. Transcripts were coded by content analysis using the World Health Organization health system building blocks (leadership/governance, financing, health workforce, health information systems, access to medicines, and service delivery). RESULTS: Thirty providers (HF:21, DO:9) and three health managers were interviewed. Eighteen providers were from HFs in the pilot-MFT area; the remaining three and all nine DOs were outside the pilot-MFT area. The analysis revealed that providers had not been trained in malaria case management in the previous twelve months. DO providers were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise DOs due to resource limitations. Providers from HFs and DOs noted poor sensitivity of malaria rapid diagnostic tests (RDTs) and hesitancy among patients who associated malaria-RDTs with HIV testing. Almost all providers reported anti-malarial stock-outs, with quinine most affected. Patient preference was a major factor in prescribing anti-malarials. Providers in HFs and DOs reported preferentially using artemether-lumefantrine in the first trimester due to the side effects and unavailability of quinine. CONCLUSION: Knowledge of malaria case management in drug outlets and health facilities remains poor. Improved regulation of DO providers is warranted. Optimizing treatment of malaria in pregnancy requires training, availability of malaria commodities, and pregnancy tests.

Women attending antenatal care as a sentinel surveillance population for malaria in Geita region, Tanzania: feasibility and acceptability to women and providers.

BACKGROUND: Measurement of malaria prevalence is conventionally estimated through infrequent cross-sectional household surveys that do not provide continuous information regarding malaria parasitaemia. Recent studies have suggested that malaria parasitaemia prevalence among women attending antenatal care (ANC) correlates with prevalence among children under 5 years old and that pregnant women could be a sentinel population for tracking malaria prevalence. In mainland Tanzania, 97% of women are tested for malaria parasitaemia during first ANC visits. However, acceptability among pregnant women and healthcare providers of collecting malaria risk factor data during ANC visits is limited. METHODS: A tablet-based questionnaire including 15 questions on insecticide-treated net ownership and use and care-seeking for febrile children was introduced at 40 healthcare facilities in Geita Region, Tanzania. Facilities were randomly selected from among those with 15-120 first ANC visits per month. To assess perspectives regarding introduction of the questionnaire, 21 semi-structured interviews were held with providers and facility in-charges at 12 facilities. Thirty pregnant and recently delivered women participated in focus group discussions at seven facilities to assess the acceptability of spending additional time answering questions about malaria risk. RESULTS: All pregnant women reported that introduction of ANC surveillance and spending 10 more minutes with providers answering questions about their health would be neutral or beneficial. They perceived being asked about their health as standard of care. Providers and in-charges reported that introduction of ANC surveillance was within their scope of practice. Nine of 21 indicated it could potentially benefit women's health. Six providers expressed concern about staffing shortages and need for reimbursement for extra time and noted that data management occurs after hours. CONCLUSIONS: Pregnant women and providers generally perceived ANC surveillance for malaria as acceptable and positive. Pregnant and recently delivered women saw this as a reasonable and even helpful intervention. To be seen as a part of standard practice, efforts are needed to ensure providers perceive a benefit for ANC clients and that staffing concerns are addressed. In addition, staff should receive feedback related to data submissions regarding malaria prevalence and risk factors among women at their facility, with actions to take.

Plasmodium falciparum infection and disease in infancy associated with increased risk of malaria and anaemia in childhood.

BACKGROUND: Infants under 6 months of age are often excluded from malaria surveillance and observational studies. The impact of malaria during early infancy on health later in childhood remains unknown. METHODS: Infants from two birth cohorts in Malawi were monitored at quarterly intervals and whenever they were ill from birth through 24 months for Plasmodium falciparum infections and clinical malaria. Poisson regression and linear mixed effects models measured the effect of exposure to malaria in infancy on subsequent malaria incidence, weight-for-age z-scores (WAZ), and haemoglobin concentrations after 6 months. RESULTS: Infants with at least one P. falciparum infection during their first 6 months had increased incidence ratio (IRR) of P. falciparum infection (IRR = 1.27, 95% CI, 1.06-1.52) and clinical malaria (IRR = 2.37, 95% CI, 2.02-2.80) compared to infants without infection. Infants with clinical malaria had increased risk of P. falciparum infection incidence between 6 and 24 months (IRR = 1.64, 95% CI, 1.38-1.94) and clinical malaria (IRR = 1.85, 95% CI, 1.48-2.32). Exposure to malaria was associated with lower WAZ over time (p = 0.02) and lower haemoglobin levels than unexposed infants at every time interval (p = 0.02). CONCLUSIONS: Infants experiencing malaria infection or clinical malaria are at increased risk of subsequent infection and disease, have poorer growth, and lower haemoglobin concentrations.

Late morning biting behaviour of Anopheles funestus is a risk factor for transmission in schools in Siaya, western Kenya.

BACKGROUND: Children in Kenya spend a substantial amount of time at school, including at dawn and dusk when mosquitoes are active. With changing vector behaviour towards early morning biting, it is important to determine whether there is an additional risk of transmission in schools. This study sought to understand whether late morning biting by Anopheles funestus, previously documented in households in western Kenya, was replicated in schools. METHODS: From the 4th to the 6th of August 2023, human landing collections were conducted hourly in four schools in Alego Usonga sub-County, Siaya County. The collections were conducted in and outside five classrooms in each school and ran for 17 h, starting at 18:00 until 11:00 h the next morning. RESULTS: Anopheles funestus was the predominant species collected, forming 93.2% (N = 727) of the entire collection, with peak landing between 06:00 and 07:00 h and continuing until 11:00 h. More than half of the collected An. funestus were either fed or gravid, potentially indicative of multiple bloodmeals within each gonotrophic cycle, and had a sporozoite rate of 2.05%. CONCLUSION: School children spend up to 10 h of their daytime in schools, reporting between 06:00 and 07:00 h and staying in school until as late as 17:00 h, meaning that they receive potentially infectious mosquito bites during the morning hours in these settings. There is a need to consider vector control approaches targeting schools and other peridomestic spaces in the morning hours when An. funestus is active.

Using antenatal care as a platform for malaria surveillance data collection: study protocol.

BACKGROUND: While many malaria-endemic countries have health management information systems that can measure and report malaria trends in a timely manner, these routine systems have limitations. Periodic community cross-sectional household surveys are used to estimate malaria prevalence and intervention coverage but lack geographic granularity and are resource intensive. Incorporating malaria testing for all women at their first antenatal care (ANC) visit (i.e., ANC1) could provide a more timely and granular source of data for monitoring trends in malaria burden and intervention coverage. This article describes a protocol designed to assess if ANC-based surveillance could be a pragmatic tool to monitor malaria. METHODS: This is an observational, cross-sectional study conducted in Benin, Burkina Faso, Mozambique, Nigeria, Tanzania, and Zambia. Pregnant women attending ANC1 in selected health facilities will be tested for malaria infection by rapid diagnostic test and administered a brief questionnaire to capture key indicators of malaria control intervention coverage and care-seeking behaviour. In each location, contemporaneous cross-sectional household surveys will be leveraged to assess correlations between estimates obtained using each method, and the use of ANC data as a tool to track trends in malaria burden and intervention coverage will be validated. RESULTS: This study will assess malaria prevalence at ANC1 aggregated at health facility and district levels, and by gravidity relative to current pregnancy (i.e., gravida 1, gravida 2, and gravida 3 +). ANC1 malaria prevalence will be presented as monthly trends. Additionally, correlation between ANC1 and household survey-derived estimates of malaria prevalence, bed net ownership and use, and care-seeking will be assessed. CONCLUSION: ANC1-based surveillance has the potential to provide a cost-effective, localized measure of malaria prevalence that is representative of the general population and useful for tracking monthly changes in parasite prevalence, as well as providing population-representative estimates of intervention coverage and care-seeking behavior. This study will evaluate the representativeness of these measures and collect information on operational feasibility, usefulness for programmatic decision-making, and potential for scale-up of malaria ANC1 surveillance.

The Effect of Intermittent Preventive Treatment of Malaria During Pregnancy and Placental Malaria on Infant Risk of Malaria.

BACKGROUND: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) provides greater protection from placental malaria than sulfadoxine-pyrimethamine (SP). Some studies suggest placental malaria alters risk of malaria infection in infants, but few have quantified the effect of IPTp on infant susceptibility to malaria. METHODS: Infants born to women enrolled in a randomized clinical trial comparing IPTp-SP and IPTp-DP in Malawi were followed from birth to 24 months to assess effect of IPTp and placental malaria on time to first malaria episode and Plasmodium falciparum incidence. RESULTS: In total, 192 infants born to mothers randomized to IPTp-SP and 195 randomized to IPTp-DP were enrolled. Infants in IPTp exposure groups did not differ significantly regarding incidence of clinical malaria (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], .58-1.86) or incidence of infection (IRR, 1.18; 95% CI, .92-1.55). Placental malaria exposure was not associated with incidence of clinical malaria (IRR, 1.03; 95% CI, .66-1.59) or infection (IRR, 1.15; 95% CI, .88-1.50). Infant sex, season of birth, and maternal gravidity did not confound results. CONCLUSIONS: We did not find evidence that IPTp regimen or placental malaria exposure influenced risk of malaria during infancy in this population. Clinical Trials Registration. NCT03009526.

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

BACKGROUND: Malaria in pregnancy doubles the risk of low birthweight; up to 11% of all neonatal deaths in sub-Saharan Africa are associated with malaria in pregnancy. To prevent these and other adverse health consequences, the World Health Organization recommends administering intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for all pregnant women at each antenatal care (ANC) visit, starting as early as possible in the second trimester. The target is for countries to administer a minimum of three doses (IPTp3+) to at least 85% of pregnant women. METHODS: A cluster randomized, controlled trial was conducted to assess the effect of delivery of IPTp by community health workers on the coverage of IPTp3 + and ANC visits in Malawi. Community delivery of IPTp was implemented within two districts in Malawi over a 21-month period, from November 2018 to July 2020. In control sites, IPTp was delivered at health facilities. Representative samples of women who delivered in the prior 12 months were surveyed at baseline (n = 370, December 2017) and endline (n = 687, August 2020). A difference in differences analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level. RESULTS: Overall IPTp coverage increased over the study period. At baseline, women received a mean of 2.3 IPTp doses (range 0-5 doses) across both arms, and at endline, women received a mean of 2.8 doses (range 0-9 doses). Despite overall increases, the change in IPTp3 + coverage was not significantly different between intervention and control groups (6.9%, 95% CI: -5.9%, 19.6%). ANC4 + coverage increased significantly in the intervention group compared with the control group, with a difference-in-differences of 25.3% points (95% CI: 1.3%, 49.3%). CONCLUSIONS: In order to reduce the burden of malaria in pregnancy, new strategies are needed to improve uptake of effective interventions such as IPTp. While community health workers' delivery of IPTp did not increase uptake in this study, they may be effective in other settings or circumstances. Further research can help identify the health systems characteristics that are conducive to community delivery of IPTp and the operational requirements for effective implementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03376217. Registered December 6, 2017, https://clinicaltrials.gov/ct2/show/NCT03376217 .

The choice of reference chart affects the strength of the association between malaria in pregnancy and small for gestational age: an individual participant data meta-analysis comparing the Intergrowth-21 with a Tanzanian birthweight chart.

BACKGROUND: The prevalence of small for gestational age (SGA) may vary depending on the chosen weight-for-gestational-age reference chart. An individual participant data meta-analysis was conducted to assess the implications of using a local reference (STOPPAM) instead of a universal reference (Intergrowth-21) on the association between malaria in pregnancy and SGA. METHODS: Individual participant data of 6,236 newborns were pooled from seven conveniently identified studies conducted in Tanzania and Malawi from 2003-2018 with data on malaria in pregnancy, birthweight, and ultrasound estimated gestational age. Mixed-effects regression models were used to compare the association between malaria in pregnancy and SGA when using the STOPPAM and the Intergrowth-21 references, respectively. RESULTS: The 10th percentile for birthweights-for-gestational age was lower for STOPPAM than for Intergrowth-21, leading to a prevalence of SGASTOPPAM of 14.2% and SGAIG21 of 18.0%, p < 0.001. The association between malaria in pregnancy and SGA was stronger for STOPPAM (adjusted odds ratio (aOR) 1.30 [1.09-1.56], p < 0.01) than for Intergrowth-21 (aOR 1.19 [1.00-1.40], p = 0.04), particularly among paucigravidae (SGASTOPPAM aOR 1.36 [1.09-1.71], p < 0.01 vs SGAIG21 aOR 1.21 [0.97-1.50], p = 0.08). CONCLUSIONS: The prevalence of SGA may be overestimated and the impact of malaria in pregnancy underestimated when using Intergrowth-21. Comparing local reference charts to global references when assessing and interpreting the impact of malaria in pregnancy may be appropriate.

Piperaquine Pharmacokinetics during Intermittent Preventive Treatment for Malaria in Pregnancy.

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.).

Acceptability of single screening and treatment policy for the control of malaria in pregnancy: perceptions of providers and pregnant women from selected health facilities in Lindi region, Tanzania.

BACKGROUND: Tanzania started implementing single screening and treatment (SST) for all pregnant women attending their first antenatal care (ANC) visits in 2014, using malaria rapid diagnostic tests (RDTs) and treating those who test positive according to the national guidelines. However, there is a paucity of data to show the acceptability of SST to both pregnant women and health care workers (HCWs), taking into consideration the shortage of workers and the added burden of this policy to the health system. This study assessed the perceptions and opinions of health service users and providers to determine the acceptability of SST policy. METHODS: Pregnant women and HCWs in eight health facilities in two districts of Lindi region (Kilwa and Lindi) were interviewed using semi-structured questionnaires with open and close-ended questions. Both qualitative and quantitative data were collected, including demographic characteristics, women's experience, their perception on SST and challenges they face when receiving services for malaria offered at ANC. Experience of HCWs regarding the implementation of SST as part of routine services and the challenges encountered when providing ANC services for malaria in pregnancy (MIP) were also assessed. RESULTS: Of the 143 pregnant women interviewed, 97% viewed testing favourably and would wish to be tested for malaria again, while 95% were satisfied with services and reasons for testing during the first ANC visit. Nearly all (99%) would recommend their fellow pregnant women to be tested for malaria and all women recommended that the Ministry of Health should continue the SST strategy. This was despite the fact that 76% of the women experienced pain and 16% had anxiety as a result of finger prick. Sixteen HCWs (mostly nurses) were interviewed; they also viewed SST implementation favourably and reported feeling empowered to use RDTs for malaria screening. The main challenge identified by HCWs was that nurses are not allowed to prescribe anti-malarials to women who test positive and need to refer them to the outpatient department for treatment. CONCLUSION: SST was considered an acceptable approach to control MIP by HCWs and pregnant women, and they recommended the continuation of the policy. In addition, consideration should be given to implementing a task-shifting policy to allow nurses to dispense anti-malarials to pregnant women.

Safety, Tolerability, and Immunogenicity of Plasmodium falciparum Sporozoite Vaccine Administered by Direct Venous Inoculation to Infants and Young Children: Findings From an Age De-escalation, Dose-Escalation, Double-blind, Randomized Controlled Study in Western Kenya.

BACKGROUND: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. METHODS: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. RESULTS: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). CONCLUSIONS: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. CLINICAL TRIALS REGISTRATION: NCT02687373.

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.

Evaluation of a single screen and treat strategy to detect asymptomatic malaria among pregnant women from selected health facilities in Lindi region, Tanzania.

BACKGROUND: In areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy. METHODS: Data from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%. RESULTS: Over the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise been missed. Among the 15.9% of women detected in the first trimester, 50.7% were asymptomatic. CONCLUSION: In areas of moderate/high transmission, many infected women were asymptomatic, and would have been missed in the absence of SST. The benefits on maternal and fetal birth outcomes of identifying these infections depend heavily on the protection afforded by treatment, which is likely to be greatest for women presenting in the first trimester when intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) is contraindicated, and in areas with high SP resistance, such as most parts of Tanzania. An evaluation of the impact and cost-effectiveness of SST across different transmission strata is warranted.

Malaria knowledge and experiences with community health workers among recently pregnant women in Malawi.

BACKGROUND: The World Health Organization recommends three or more doses of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) to mitigate the negative effects of malaria in pregnancy (MIP). Many pregnant women in Malawi are not receiving the recommended number of doses. Community delivery of IPTp (cIPTp) is being piloted as a new approach to increase coverage. This survey assessed recently pregnant women's knowledge of MIP and their experiences with community health workers (CHWs) prior to implementing cIPTp. METHODS: Data were collected via a household survey in Ntcheu and Nkhata Bay Districts, Malawi, from women aged 16-49 years who had a pregnancy resulting in a live birth in the previous 12 months. Survey questions were primarily open response and utilized review of the woman's health passport whenever possible. Analyses accounted for selection weighting and clustering at the health facility level and explored heterogeneity between districts. RESULTS: A total of 370 women were interviewed. Women in both districts found their community health workers (CHWs) to be helpful (77.9%), but only 35.7% spoke with a CHW about antenatal care and 25.8% received assistance for malaria during their most recent pregnancy. A greater proportion of women in Nkhata Bay than Ntcheu reported receiving assistance with malaria from a CHW (42.7% vs 21.9%, p = 0.01); women in Nkhata Bay were more likely to cite IPTp-SP as a way to prevent MIP (41.0% vs 24.8%, p = 0.02) and were more likely to cite mosquito bites as the only way to spread malaria (70.6% vs 62.0% p = 0.03). Women in Nkhata Bay were more likely to receive 3 + doses of IPTp-SP (IPTp3) (59.2% vs 41.8%, p = 0.0002). Adequate knowledge was associated with increased odds of receiving IPTp3, although not statistically significantly so (adjusted odds ratio = 1.50, 95% confidence interval 0.97-2.32, p-value 0.066). CONCLUSIONS: Women reported positive experiences with CHWs, but there was not a focus on MIP. Women in Nkhata Bay were more likely to be assisted by a CHW, had better knowledge, and were more likely to receive IPTp3+ . Increasing CHW focus on the dangers of MIP and implementing cIPTp has the potential to increase IPTp coverage.