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.

Uptake of intermittent preventive treatment of malaria in pregnancy and risk factors for maternal anaemia and low birthweight among HIV-negative mothers in Dschang, West region of Cameroon: a cross sectional study.

BACKGROUND: Approximately 32 million pregnant women are at risk of malaria with up to 10,000 maternal deaths and 200,000 neonates at risk annually. Intermittent Preventive Treatment (IPT) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization (WHO) to reduce disease in pregnancy and adverse maternal and newborn outcomes. At least three doses of SP should be taken by pregnant women during antenatal consultation (ANC) beginning from the thirteenth week of pregnancy till parturition. The aim of this study was to assess uptake of IPT during pregnancy and risk factors for maternal anaemia and infant birth weight in Dschang, West region of Cameroon. METHODS: A total of 380 consenting pregnant women at delivery were recruited in a cross- sectional prospective survey between January to December 2021. Data on ANC attendance, total dose of IPT and history of malaria were abstracted from hospital ANC records while socio-demographic characteristics, bed net use and obstetrics history of each participant were also recorded through an interview. Further, blood samples were collected from the intervillous space for assessment of maternal anaemia and microscopic parasitology. Nested PCR based on amplification of the Plasmodium 18S sRNA was carried out to detect submicroscopic infection. IPTp coverage was calculated per WHO recommendation and the prevalence of anaemia and low birth weight were estimated as proportions in the total sample of pregnant women and live births, respectively. Crude and adjusted odds ratios and their 95% confidence intervals were used to estimate associations between pregnancy outcomes considered and risk factors in specific and general models. A p < 0.05 was considered significant. The R software (V4.1.4) was used for all analyses. RESULTS: A majority of pregnant women was aged between 24 and 34 years old (59.2%) and had secondary education (58.8%). Uptake of ≥ 3 IPTp was 64.99% with 77.20% of all who received at least one IPTp doses taking a mix of SP and DP or DP alone in successive ANC contacts. Those with four or more ANC contacts (73.42%) were more likely to have received at least one IPTp. Furthermore, 13.9% of live births had low birthweights (BW < 2500 g) and one in four parturient women with moderate anaemia by WHO criteria. Microscopy (blood smear examination) and PCR-based diagnosis revealed between 0% and 1.57% of parasite-infected placental samples, respectively. Reported malaria in pregnancy predicted maternal anaemia at birth but not birth weight. Only gestational age (< 37 weeks) and bed net use (< 5 months) significantly predicted infant birth weight at delivery. CONCLUSION: The uptake of WHO recommended IPT doses during pregnancy was moderately high. Reported malaria in pregnancy, poor bed net coverage, gestational age less than 37 weeks adversely affect maternal haemoglobin levels at birth and infant birth weight. Asymptomatic and submicroscopic placental parasite infections was found at low prevalence. Together these results highlight the importance of maintaining aggressive measures to prevent malaria in pregnancy and protect the health of mother and baby.

Impact of Intermittent Presumptive Treatment for Malaria in Pregnancy on Hospital Birth Outcomes on the Kenyan Coast.

BACKGROUND: Intermittent preventive treatment (IPTp) for pregnant women with sulfadoxine-pyrimethamine (SP) is widely implemented for the prevention of malaria in pregnancy and adverse birth outcomes. The efficacy of SP is declining, and there are concerns that IPTp may have reduced impact in areas of high resistance. We sought to determine the protection afforded by SP as part of IPTp against adverse birth outcomes in an area with high levels of SP resistance on the Kenyan coast. METHODS: A secondary analysis of surveillance data on deliveries at the Kilifi County Hospital between 2015 and 2021 was undertaken in an area of low malaria transmission and high parasite mutations associated with SP resistance. A multivariable logistic regression model was developed to estimate the effect of SP doses on the risk of low birthweight (LBW) deliveries and stillbirths. RESULTS: Among 27 786 deliveries, 3 or more doses of IPTp-SP were associated with a 27% reduction in the risk of LBW (adjusted odds ratio [aOR], 0.73; 95% confidence interval [CI], .64-.83; P < .001) compared with no dose. A dose-response association was observed with increasing doses of SP from the second trimester linked to increasing protection against LBW deliveries. Three or more doses of IPTp-SP were also associated with a 21% reduction in stillbirth deliveries (aOR, 0.79; 95% CI, .65-.97; P = .044) compared with women who did not take any dose of IPTp-SP. CONCLUSIONS: The continued significant association of SP on LBW deliveries suggests that the intervention may have a non-malaria impact on pregnancy outcomes.

Status of malaria in pregnancy services in Madagascar 2010-2021: a scoping review.

BACKGROUND: Malaria in pregnancy (MIP) increases the risk of poor maternal and infant outcomes. To reduce these risks, WHO recommends insecticide-treated net (ITN) use, intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), and prompt case management. However, uptake of these interventions remains sub-optimal in Madagascar. A scoping review was conducted to determine the breadth and depth of information available during 2010-2021 about Madagascar's MIP activities and to identify barriers and facilitators to MIP interventions uptake. METHODS: PubMed, Google Scholar, and USAID's files (Development Experience Catalog) were searched using the terms "Madagascar AND pregnancy AND malaria," and reports and materials from stakeholders were collected. Documents in English and French from 2010 to 2021 with data regarding MIP were included. Documents were systematically reviewed and summarized; results were captured in an Excel database. RESULTS: Of 91 project reports, surveys and published articles, 23 (25%) fell within the stated time period and contained relevant data on MIP activities in Madagascar and were categorized accordingly: eight (35%) quality of care, including health facility readiness, provider knowledge and commodity availability; nine (39%) care-seeking behaviour; and, six (26%) prevention of MIP. Key barriers were identified: nine articles mentioned SP stockouts; seven found limitations of provider knowledge, attitudes, and behaviours (KAB) regarding MIP treatment and prevention; and, one reported limited supervision. MIP care seeking and prevention barriers and facilitators included women's KAB regarding MIP treatment and prevention, distance, wait times, poor service quality, cost, and/or unwelcoming providers. A 2015 survey of 52 health facilities revealed limited client access to antenatal care due to financial and geographic barriers; two 2018 surveys revealed similar findings. Self-treatment and care-seeking delays were reported even when distance was not a barrier. CONCLUSION: Among the studies and reports on MIP in Madagascar, the scoping review frequently noted barriers that could be mitigated by reducing stockouts, improving provider knowledge and attitudes, refining MIP communication, and improving service access. There is a need for coordinated efforts to address the identified barriers is the key implication of the findings.

Strengthening the capacity of healthcare providers to administer intermittent preventive therapy for malaria in pregnancy in Nigeria using a quality improvement strategy.

BACKGROUND: Intermittent Preventive Therapy using Sulfadoxine Pyrimethamine (IPTp-SP) is a malaria control strategy to reduce cases of malaria in pregnancy in endemic countries. However, the administration of the recommended three doses of Intermittent Preventive Therapy (IPTp) throughout the stages of pregnancy still remains low in Nigeria. Limited knowledge by health workers on the administration of the recommended doses of IPTp to pregnant women receiving antenatal care (ANC) services is partly responsible for this gap. This study applied Quality Improvement (QI) approach to improve knowledge and practice among healthcare providers with respect to the administration of IPTp-SP. METHODS: A quasi-experimental study design was carried out to evaluate the effect of QI approach consisting of training and coaching of healthcare providers to improve the administration of IPTp during ANC services. Primary Healthcare Centre Samaru was purposively selected and 11 healthcare providers participated in the study. The total duration of the intervention was for a period of 4 weeks which comprises of four training sessions conducted over a period of 2 weeks and four coaching sessions conducted for a period of another 2 weeks. The training package involved the use of the Information, Education and Communication approach of healthcare providers on IPTp administration while the coaching package involved supervision and follow-up meetings guiding healthcare providers on the protocol of IPTp administration. Antenatal care daily register was reviewed pre-intervention, intervention and post-intervention period of the study. Data were analysed using line graphs and run charts. RESULTS: A total of 36 ANC visit weeks were observed between 21 November 2016 and 27 July 2017. There was overestimation of first dose of IPTp (IPTp1) as 8 of the 16 Weeks in the pre-intervention period had more than 100% of eligible women administered IPTp1. There was evidence indicating the process of IPTp1 was relatively stable post-intervention as the data crosses the median line only six times that is, 7 runs. This indicates that the process of IPTp1 was within normal variation over the post-intervention period. The patterns of IPTp2+ administrations shows the levels of IPTp2+ administration were erratic. There was an upward shift showing immediate improvement of the administration of IPTp2+ post-intervention. CONCLUSIONS: The integrated training and coaching intervention approach improved the administration of the recommended three doses of IPTp within the context of a Primary Healthcare Centre. The data quality of the ANC daily register improved post-intervention.

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.

Pregnancy and malaria: the perfect storm.

PURPOSE OF REVIEW: Malaria in pregnancy continues to exert a toll on pregnant women and their offspring. RECENT FINDINGS: The burden of Plasmodium falciparum infection is especially large in Africa, and new data show lasting effects of maternal infection on the infant's neurocognitive development. Elsewhere, P. vivax infection causes relapsing infections that are challenging to prevent. Infection in first trimester of pregnancy is an area of increasing focus, and its adverse effects on pregnancy outcome are increasingly recognised. First-trimester infection is common and frequently acquired prior to conception. Although newer rapid diagnostic tests still have limited sensitivity, they may be useful in detection of early pregnancy malaria for treatment. Artemisinin-based combination therapies are efficacious in later pregnancy but have yet to be recommended in first trimester because of limited safety data. In Africa, intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine improves pregnancy outcomes, but sulfadoxine-pyrimethamine resistance is worsening. The alternative, IPTp with dihydroartemisinin-piperaquine, has greater antimalarial efficacy, but does not appear to improve pregnancy outcomes, because sulfadoxine-pyrimethamine has poorly understood nonmalarial benefits on birthweight. SUMMARY: Novel IPTp regimens must be combined with interventions to strengthen protection from malaria infection acquired before and in early pregnancy.

Effect of dihydroartemisinin/piperaquine for malaria intermittent preventive treatment on dolutegravir exposure in pregnant women living with HIV.

BACKGROUND: In sub-Saharan Africa, the burdens of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PLWH) require both ART and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin/piperaquine has been identified as a promising alternative to sulfadoxine/pyrimethamine for IPTp. However, another antimalarial drug, artesunate/amodiaquine, similar to dihydroartemisinin/piperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults. OBJECTIVES: To investigate the effect of dihydroartemisinin/piperaquine on dolutegravir plasma exposure in pregnant women on dolutegravir-based ART. METHODS: We conducted an open-label, non-randomized, fixed-sequence, pharmacokinetic study in PLWH in Malawi. Dolutegravir concentrations were measured over a 24 h period, before and after the recommended 3 day treatment dose of dihydroartemisinin/piperaquine in 12 pregnant women in their second or third trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% CIs were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods. RESULTS: Co-administration of dihydroartemisinin/piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24) and Cmax by 30% (GMR 1.30; 90% CI 1.11-1.52) and 31% (GMR 1.31; 90% CI 1.13-1.51), respectively. The dolutegravir trough (C24) concentration increased by 42% (GMR 1.42; 90% CI 1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed. CONCLUSIONS: Dihydroartemisinin/piperaquine may be administered with dolutegravir-based ART in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, ensures its efficacy without any clinically significant adverse events observed in this small study.

A qualitative assessment of the health systems factors influencing the prevention of malaria in pregnancy using intermittent preventive treatment and insecticide-treated nets in Ghana.

BACKGROUND: Ghana has adopted and implemented intermittent preventive treatment using sulfadoxine-pyrimethamine (IPTp-SP) and insecticide-treated nets (ITNs) in an antenatal care (ANC) context to prevent malaria among pregnant women. However, the increased ANC attendance and its frequency facilitated by a free maternal health care policy in Ghana does not correspond with the uptake of IPTp-SP and ITN use among pregnant women. This study sought to elucidate the contextual health system factors influencing the delivery of IPTp-SP and ITN from a related quantitative study conducted in Ghana. METHODS: This is the qualitative section of a mixed-methods study design, where audio recorded key informant interviews (KIIs) were conducted with health workers from across health facilities, districts, regional and national health directorates. The KIIs elicited information on health worker knowledge, perceptions, and rationale for the delivery practices of IPTp-SP and ITN revealed in the quantitative findings. The interviews were transcribed and imported into NVivo for analysis. Using the World Health Organization (WHO) Health Systems Framework as the theoretical basis, thematic analysis was conducted under broad themes of the building blocks. Findings are presented in narrative quotes, with a mindmap used to summarize the various health system factors and their interrelated relationship influencing the delivery of IPTp-SP and ITN. RESULTS: Health system factors identified included health staff untrained on malaria delivery directives due to an ineffective trainer of trainer (ToT) system. Additionally, health worker confusion on when to commence SP (at quickening or ≥ 16 weeks) was found to result in delayed start of SP. Stock-outs in facilities due to procurement delays at the national level resulted in missed opportunities to deliver SP to eligible pregnant women at the ANC. Similarly, ITN stock outs led to eligible pregnant women not receiving one at ANC clinics. CONCLUSION: Poor health worker knowledge on policy directives, a consequence of ineffective training strategy led to delayed delivery of IPTp-SP to eligible pregnant women. Supply chain management challenges related to stock of SP and ITN resulted in missed opportunities to deliver the interventions to pregnant women attending ANC.

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 .

Factors influencing health workers' compliance with the WHO intermittent preventive treatment for malaria in pregnancy recommendations in the Northern Region, Ghana.

BACKGROUND: Although IPTp-SP is a lifesaving World Health Organization (WHO) recommended preventive intervention for pregnant women in malaria-endemic regions, IPTp-SP uptake in the Northern region of Ghana is much lower than the sub-optimal national coverage level. Assessing the extent of health workers' compliance and its associated factors will generate valuable pointers to be targeted at the program level. The study examined the factors influencing health workers' compliance with the WHO recommended guidelines for IPTp-SP in the Northern Region. METHODS: A cross-sectional study among 315 health workers in the Northern region was conducted. Semi-structured questionnaires were used to collect data on health workers' sociodemographic characteristics, facility-based factors and knowledge level. Data were collected on health workers' compliance with the recommended practices through covert observations using a checklist. Facility observations were carried out using a checklist. Crude and adjusted logistic regression were used to determine predictors of health workers' compliance, at a 5% significance level adjusting for clustering. RESULTS: Of the 315 health workers studied, the median age was 29 years (26-34 years). Females constituted (80.5%; 252) of the 313 workers. The majority (47.4%;148) of the 312 health workers were midwives. Overall, 56.2% (CI 51.0 - 62.0) were adequately complying with the recommended guidelines. Lower levels of compliance were recorded in health centres 15.6% (5.0 - 33.0) and CHPS compounds 21.2% (11.0 - 35.0). The factors associated with compliance included health workers' knowledge (aOR = 7.64, 95% CI 4.21 - 13.87, p < 0.001), job satisfaction (aOR 10.87, 95% CI 7.04 - 16.79, p < 0.001), in-service training (aOR 10.11, 95% CI 4.53 - 22.56, p < 0.001), supervision (aOR 4.01, 95% CI 2.09 - 7.68, p < 0.001), availability of job aids (aOR 3.61, 95% CI 2.44 - 5.35, p < 0.001), health workers experience (aOR = 10.64, 95% CI 5.99 - 18.91, p < 0.001) and facility type (aOR 0.03, 95% CI 0.01-0.07, p < 0.001). CONCLUSION: Compliance with the recommended IPTp-SP guidelines is suboptimal in the region, with lower-level health facilities recording the least compliance levels. Health centres and CHPS facilities should be prioritized in distributing limited resources to improve health worker quality of care for antenatal care clients.

Uptake of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in Uganda: a national survey.

BACKGROUND: In spite of the missed opportunities of sulfadoxine-pyrimethamine (IPTp-SP) in Uganda, scanty literature exist on malaria in pregnancy. To date, empirical national study utilizing the 2018-19 Uganda Malaria Indicator Survey to explore predictors of attaining three or more doses of IPTp-SP in the country is non-existent. This study investigated the factors affecting uptake of three or more IPTp-SP doses as recommended by the World Health Organization. METHODS: Data from the 2018-2019 Uganda Malaria Indicator Survey (2018-19 UMIS) was analysed. Adequate uptake of intermittent preventive therapy with IPTp-SP was the dependent variable for this study. Weighted frequencies and percentages were used to present the proportion of women who had adequate IPTp-SP uptake or otherwise with respect to the independent variables. A three-level multilevel logistic regression was fitted. The Bayesian Deviance Information Criterion (DIC) was used in determining the goodness of fit of all the models. RESULTS: Less than half of the surveyed women had three or more IPTp-SP doses during their last pregnancies (45.3%). Women aged 15-19 had less odds of receiving at least three IPTp-SP doses compared to those aged 45-49 [aOR = 0.42, Crl = 0.33-0.98]. Poor women [aOR = 0.80, Crl = 0.78-0.91] were less likely to have three or more doses of IPTp-SP relative to rich women. Most disadvantaged regions were aligned with less likelihood of three or more IPTp-SP uptake [aOR = 0.59, CI = 0.48-0.78] compared to least disadvantaged regions. The variation in uptake of three or more IPTp-SP doses was substantial at the community level [σ2 = 1. 86; Crl = 11.12-2.18] than regional level [σ2 = 1.13; Crl = 1.06-1.20]. About 18% and 47% disparity in IPTp-SP uptake are linked to region and community level factors respectively. CONCLUSION: IPTp-SP interventions need to reflect broader community and region level factors in order to wane the high malaria prevalence in Uganda. Contextually responsive behavioural change communication interventions are required to invoke women's passion to achieve the recommended dosage.

Variations in the use of malaria preventive measures among pregnant women in Guinea: a secondary analysis of the 2012 and 2018 demographic and health surveys.

BACKGROUND: Despite its effectiveness, the optimal use of the combination of insecticide-treated nets (ITN) and intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) remains low in malaria-endemic areas. Therefore, this study analyzed its variations and predictors in Guinea. METHODS: This study was a secondary analysis of the 2012 and 2018 Guinea Demographic and Health Surveys (DHS). It included women who had given birth 3 years before each DHS, slept on ITN and took at least one dose of SP. Use was complete if a pregnant woman slept on ITNs and took SP (at least two doses in 2012; at least three doses in 2018). Moran indices were used to determine spatial autocorrelation and classification methods to identify malaria preventive measures (MPM) predictors. RESULTS: In 2012, 60.88% of pregnant women had incomplete use of MPMs compared with 79.11% in 2018. Associated factors with incomplete MPMs in 2012 were as follows: having an indirect link with the head of household (AOR = 2.23, 95% CI 1.08-4.61) and performing at least 4 ANC visits (AOR = 0.66, 95% CI 0.44-0.99). In 2018: Living in households of 2 to 5 people (AOR = 0.54, 95% CI 0.36-0.80), have a man as the head of the household (AOR = 0.56, 95% CI 0.35-0.89), perform the first ANC in the second trimester of pregnancy (AOR = 0.74, 95% CI 0.54-0.99), perform at least 4 ANC visits (AOR = 0.47, 95% CI 0.36-0.62), have a job (AOR = 0. 67, 95% CI 0.50-0.88), give birth in a public health facility (AOR = 0.53, 95% CI 0.39-0.72) and the middle wealth quintile (AOR = 1.56, 95% CI 1.07-2.26). Analyses revealed a global autocorrelation (Moran index = 0.0009, p = 0.2349) and high-high clusters in Mamou in 2012. In 2018, autocorrelation was found (I Moran = 0.0169, p ≤ 0.05), with spatial clusters in 4 regions. CONCLUSION: The link with the head of household and the number of ANC visits were the main factors in MPMs. It is essential to implement strategies at the household level and health system level and monitor them to reduce inequality across regions.

Determinants of utilization of malaria preventive measures during pregnancy among women aged 15 to 49 years in Kenya: an analysis of the Malaria Indicator Survey 2020.

BACKGROUND: Malaria is a significant cause of morbidity and mortality. Malaria infection in pregnancy can have severe consequences for the fetus and the mother. To fight against malaria infection in pregnancy, Kenya integrated the issuance of an insecticide-treated net (ITN) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTpSP) with antenatal care (ANC) for pregnant women. However, the uptake of the ITN and IPTpSP is still low. Individual, social, or structural factors may influence the low uptake. It is, therefore, important to identify the determinants associated with the uptake of ITN and IPTpSP during pregnancy in Kenya. METHODS: Data were from the 2020 Kenya Malaria Indicator Survey (MIS). A total of 1779 women between the ages of 15 to 49 years who had a history of either being pregnant or having given birth within 5 years before the MIS survey were included. Survey-adjusted multinomial logistic regression was used in the analysis. RESULTS: During pregnancy, ITN use was more than half (54.9%). The use of at least one dose of IPTpSP was 43.5%, three or more doses of IPTpSP was 27.2%, and only 28.2% of the participants used both ITN and IPTpSP during pregnancy. The significant determinants of combined use of ITN and IPTpSP during pregnancy were maternal age (RR 3.57, CI 1.80-7.08; p=<0.001), maternal education (RRR 2.84, CI 1.33-6.06; p=0.007), wealth index (RR 2.14, CI 1.19-3.84; p=0.011) and living in the different malaria epidemiological zones: lake endemic (RRR 10.57 CI 5.65-19.76; p=<0.001), coastal endemic area (RRR 4.86 CI 1.86-12.67; p=0.001), seasonal (RRR 0.21 CI 0.10-0.39; p=<0.001) and low risk (RRR 0.07, CI 0.03-0.17; p=<0.001). CONCLUSION: The uptake of malaria preventive measures is still below 80% for both ITN and IPTpSP during pregnancy in Kenya. The significant results on determinants of the use of ITN and IPTpSP could be considered in implementing malaria prevention programmes during pregnancy. For example, sensitizing the community on the importance of antenatal care visits will provide a platform to teach the importance of malaria prevention in pregnancy. Moreover, the pregnant mothers receive an ITN and IPTpSP during the ANC visit.

Malaria in pregnancy control and pregnancy outcomes: a decade's overview using Ghana's DHIMS II data.

BACKGROUND: Malaria in pregnancy control interventions have been implemented through antenatal care services for more than 2 decades in Ghana. The uptake of these interventions has seen steady improvement over the years. This has occurred within the context of decreasing global trends of malaria infection confirmed by decreasing malaria in pregnancy prevalence in Ghana. However, not much is known about how these improvements in interventions uptake and reduction in malaria infection prevalence have impacted pregnancy outcomes in the country. This study aimed at describing trends of maternal anaemia and low birth weight prevalence and uptake of malaria in pregnancy control interventions over the last decade using data from Ghana's District Health Information Management System (DHIMS II). METHODS: Data from Ghana's DHIMS II on variables of interest covering the period 2012 to 2021 was analysed descriptively using Microsoft Excel 365. Results were computed as averages and percentages and presented in tables and graphs. RESULTS: The prevalence of maternal anaemia at booking and at term and low birth weight increased marginally from 31.0%, 25.5% and 8.5% in 2012 to 36.6%, 31.9% and 9.5% in 2021 respectively. Severe anaemia prevalence at booking and at term remained under 2% over the study period. Women making at least 4 ANC visits, receiving at least 3 doses of intermittent preventive treatment of malaria and an insecticide-treated net increased from 77.0%, 41.4% and 4.1% in 2012 to 82%, 55.0% and 93.3% in 2021, respectively. Malaria test positivity rate reduced from 54.0% to 34.3% between 2014 and 2021 while women receiving iron and folate supplementation for 3 and 6 months rose from 43.0% and 25.5% to 89.7% and 61.8%, respectively between 2017 and 2021. CONCLUSION: Maternal anaemia and low birth weight prevalence showed marginal upward trends over the last decade despite reduced malaria infection rate and improved uptake of malaria in pregnancy control interventions. There is room for improvement in current intervention implementation levels but the complex and multi-factorial aetiologies of maternal anaemia and low birth weight need urgent investigation and quantification to inform policy and practice.

Reduced Birth Weight Caused by Sextuple Drug-Resistant Plasmodium falciparum Infection in Early Second Trimester.

Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps, particularly the sextuple mutant haplotype threatens the antimalarial effectiveness of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment during pregnancy (IPTp). To explore the impact of sextuple mutant haplotype infections on outcome measures after provision of IPTp with SP, we monitored birth outcomes in women followed up from before conception or from the first trimester until delivery. Women infected with sextuple haplotypes, in the early second trimester specifically, delivered newborns with a lower birth weight compared with women who did not have malaria during pregnancy (difference, -267 g; 95% confidence interval, -454 to -59; P = .01) and women infected with less SP-resistant haplotypes (-461 g; -877 to -44; P = .03). Thus, sextuple haplotype infections seem to affect the effectiveness of SP for IPTp and directly affect birth outcome by lowering birth weight. Close monitoring and targeted malaria control during early pregnancy is therefore crucial to improving birth outcomes.

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.

Malaria Infection Is Common and Associated With Perinatal Mortality and Preterm Delivery Despite Widespread Use of Chemoprevention in Mali: An Observational Study 2010 to 2014.

BACKGROUND: In malaria-endemic areas, pregnant women and especially first-time mothers are more susceptible to Plasmodium falciparum. Malaria diagnosis is often missed during pregnancy, because many women with placental malaria remain asymptomatic or have submicroscopic parasitemia, masking the association between malaria and pregnancy outcomes. Severe maternal anemia and low birthweight deliveries are well-established sequelae, but few studies have confirmed the relationship between malaria infection and severe outcomes like perinatal mortality in high transmission zones. METHODS: Pregnant women of any gestational age enrolled at antenatal clinic into a longitudinal cohort study in Ouelessebougou, Mali, an area of high seasonal malaria transmission. Follow-up visits included scheduled and unscheduled visits throughout pregnancy. Blood smear microscopy and polymerase chain reaction (PCR) analysis were employed to detect both microscopic and submicroscopic infections, respectively. Intermittent preventative treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) was documented and prompt treatment regardless of symptoms given upon malaria diagnosis. RESULTS: Of the 1850 women followed through delivery, 72.6% of women received 2 or more IPTp-SP doses, 67.2% of women experienced at least 1 infection between enrollment up to and including delivery. Malaria infection increased the risks of stillbirth (adjusted hazard ratio [aHR] 3.87, 95% confidence interval [CI]: 1.18-12.71) and preterm delivery (aHR 2.41, 95% CI: 1.35-4.29) in primigravidae, and early neonatal death (death within 7 days) in secundigravidae and multigravidae (aHR 6.30, 95% CI: 1.41-28.15). CONCLUSIONS: Malaria treatment after diagnosis, alongside IPTp-SP, is insufficient to prevent malaria-related stillbirth, early neonatal death and preterm delivery (PTD). Although IPTp-SP was beneficial in Mali during the study period, new tools are needed to improve pregnancy outcomes. CLINICAL TRIALS REGISTRATION: NCT01168271.

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.).

Cotrimoxazole versus sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria in HIV-infected pregnant women in Bangui, Central African Republic: A pragmatic randomised controlled trial.

OBJECTIVE: The main objective of the MACOMBA (Maternity and Control of Malaria-HIV co-infection in Bangui) trial was to show that cotrimoxazole (CTX) is more effective than sulphadoxine-pyremethamine-IPTp (IPTp-SP) to prevent placental malaria infection (primary end point) among HIV-positive pregnant women with a CD4+ count ≥350 cells/mm3 in Bangui, CAR. METHODS: MACOMBA is a multicentre, open-label randomised trial conducted in four maternity hospitals in Bangui. Between 2013 and 2017, 193 women were randomised and 112 (59 and 53 in CTX and IPTp-SP arms, respectively) were assessed for placental infection defined by microscopic parasitaemia or PCR. RESULTS: Thirteen women had a placental infection: five in the CTX arm (one by microscopic placental parasitaemia and four by PCR) and eight by PCR in the SP-IPTp (8.5% vs. 15.1%, p = 0.28). The percentage of newborns with low birthweight (<2500 g) did not differ statistically between the two arms. Self-reported compliance to CTX prophylaxis was good. There was a low overall rate of adverse events in both arms. CONCLUSION: Although our results do not allow us to conclude that CTX is more effective, drug safety and good compliance among women with this treatment favour its widespread use among HIV-infected pregnant women, as currently recommended by WHO.