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Harry Tagbor,1 Gifty Antwi,1 Joslin Dogbe21Department of Community Health, 2Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, GhanaIntroduction: Inadequately controlled malaria infection in pregnancy is associated with poor maternal and fetal outcomes. However, there are important questions about drug safety for mothers with malaria and their fetuses as, currently, there is limited safety data on many of the medications used. The objective of this review is to determine from published evidence the safety of antimalarial drugs exposure during early pregnancy, focusing on abortions, stillbirths, and congenital abnormalities.Methods: We searched PubMed, Embase, Cochrane Library, and Malaria in Pregnancy databases from their inception to June 2013, inclusive, for reports published in English only. Data were extracted on exposure to antimalarial drugs during early pregnancy and adverse pregnancy outcomes including congenital abnormalities, stillbirth, and miscarriage.Results: Twenty-two publications including one abstract with a total of 6,333 early pregnancy exposures to antimalarial agents used for treatment and/or prevention of malaria in pregnancy met the inclusion criteria. More than 40% of the pregnancies were exposed to mefloquine, about 10% to artemisinin based regimens and, 15.2% and 14.7% were exposed to chloroquine and quinine, respectively. A total of 1,199 adverse outcomes including abortions, stillbirths, and congenital abnormalities were reported. The reported absolute risks of adverse outcomes were similar for all the antimalarial exposures, but, in two publications, increased risk of stillbirths was linked to mefloquine exposure. Extensive heterogeneity and variability in the way in which authors assessed, recorded, and reported safety data precluded formal meta-analysis.Conclusion: The absolute estimates of risks obtained in the included studies are difficult to interpret and the clinical significance of any association of adverse outcomes reported with antimalarial exposure in early pregnancy is uncertain. Well planned, executed, and analyzed studies are needed to confirm whether there is increased risk for adverse fetal outcomes attributable to exposure of first trimester pregnancies to antimalarials compared to relevant controls.Keywords: malaria in pregnancy, first trimester, antimalarials, adverse outcomes, mefloquine, congenital abnormalities

Abstract Background Malaria in pregnancy is associated with increased risks of maternal and foetal complications. Currently, intermittent preventive treatment (IPT) of malaria during pregnancy with sulphadoxine-pyrimethamine (SP) is recommended by the WHO as part of a package of interventions also including insecticide-treated nets and effective case management. However, with increasing resistance to SP, the effectiveness of SP-IPT has been questioned. A randomized controlled trial (RCT) to investigate the relative efficacy of an alternative strategy of intermittent screening and treatment (IST), which involves a rapid diagnostic test for malaria at scheduled ANC visits and treatment of women only if positive, versus SP-IPT has been conducted in Ashanti region, Ghana. This paper reports on a complementary study investigating the acceptability of the different strategies to women enrolled in the trial. Methods Data were collected through twelve focus group discussions with women selected at random from the different arms of the RCT, exploring their experiences and perceptions about antenatal care and their involvement in the trial. Content analysis was used to identify relevant themes to structure the results. Results Five main themes emerged from participants' experiences of ANC and the RCT that would influence their acceptability of malaria prevention strategies during pregnancy: health benefits; drugs received; tests received; other services received; and health worker attitude. Their own health and that of their baby were strong motivations for attending ANC, and reported favourably as an outcome of being in the RCT. Women were not always clear on the biomedical function of drugs or blood tests but generally accepted them due to strong trust in the health staff. Home visits by staff and free ITNs as part of the trial were appreciated. Politeness and patience of health staff was a very strong positive factor. Conclusions Overall, both intermittent screening and treatment and intermittent preventive treatment appeared equally acceptable to pregnant women as strategies for the control of malaria in pregnancy. The women were more concerned about quality of services received, in particular the polite and patient attitude of health staff, and positive health implications for themselves and their babies than about the nature of the intervention.

Artemisinin-based combination therapy (ACT) is the first-line recommended treatment for uncomplicated malaria. Pharmacokinetic (PK) properties in pregnant women are often based on small studies and need to be confirmed and validated in larger pregnant patient populations. This study aimed to evaluate the PK properties of amodiaquine and its active metabolite, desethylamodiaquine, and piperaquine in women in their second and third trimester of pregnancy with uncomplicated P. falciparum infections. Eligible pregnant women received either artesunate-amodiaquine (200/540 mg daily, n = 771) or dihydroartemisinin-piperaquine (40/960 mg daily, n = 755) for 3 days (NCT00852423). Population PK properties were evaluated using nonlinear mixed-effects modeling, and effect of gestational age and trimester was evaluated as covariates. 1071 amodiaquine and 1087 desethylamodiaquine plasma concentrations, and 976 piperaquine plasma concentrations, were included in the population PK analysis. Amodiaquine concentrations were described accurately with a one-compartment disposition model followed by a two-compartment disposition model of desethylamodiaquine. The relative bioavailability of amodiaquine increased with gestational age (1.25% per week). The predicted exposure to desethylamodiaquine was 2.8%-32.2% higher in pregnant women than that reported in non-pregnant women, while day 7 concentrations were comparable. Piperaquine concentrations were adequately described by a three-compartment disposition model. Neither gestational age nor trimester had significant impact on the PK of piperaquine. The predicted exposure and day 7 concentrations of piperaquine were similar to that reported in non-pregnant women. In conclusion, the exposure to desethylamodiaquine and piperaquine was similar to that in non-pregnant women. Dose adjustment is not warranted for women in their second and their trimester of pregnancy., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction . Fungal infections are relevant health risks for individuals with acquired immunodeficiency in the resource-limited tropics, but available surveillance data are scarce. For Candida auris and Cryptococcus spp., the evolution from environmental reservoirs to human pathogens causing life-threatening diseases is currently discussed as a public health concern in the context of climate change and limited treatment options. Gap statement . Uncovering the gastrointestinal tract as an epidemiological niche of fungi emerging from the environment into individuals for whom fungal infections are not diagnosed. Aim . To contribute to data on the local epidemiology of C. auris and Cryptococcus spp. in Western African Ghana by analysing gastrointestinal samples of Ghanaian individuals. Methodology . Four real-time PCR assays targeting C. auris and five real-time PCR assays targeting Cryptococcus spp. were applied with stool samples of 875 non-age-stratified Ghanaian HIV patients and 30 Ghanaian control individuals without known HIV infection. Also, 664 samples from Ghanaian children under 2 years of age were investigated. The true abundance of the target micro-organism was considered as unlikely in the case of one or fewer positive signals, likely in the case of two to three positive signals and highly likely in the case of four or more positive signals per sample in the real-time PCR assays. Results . The combined application of sensitive, target-specific real-time PCR assays indicates that neither C. auris , Cryptococcus neoformans complex nor Cryptococcus gattii complex were part of the gut microbiota of Ghanaian individuals with or without HIV infection. Conclusion . Despite the significant disease burden from these pathogens in immunosuppressed Ghanaian individuals, detection from gastrointestinal samples was unlikely, which should be taken into account when discussing screening strategies for these fungi of public health concern. In contrast, the detection of these fungi from such samples should not routinely be considered as commensal colonization flora.

The study was conducted to identify cluster patterns of enteric microorganisms with potential etiological relevance for infectious gastroenteritis in stool samples of individuals from Ghana, which is a known high-endemicity setting for infectious gastroenteritis. These patterns were compared to previous observations with specimens from Colombian indigenous people in order to assess potentially stable clustering for temporally and spatially distinct populations from high-endemicity regions. By doing so, the study aimed to identify stable clusters as markers of microbial interaction with potential importance for etiological relevance assignment in cases of multiple enteric pathogen detections. Stool samples from 1569 Ghanaian individuals (875 from HIV patients, 30 from HIV-negative control adult patients, and 644 from children < 2 years of age) were assessed for enteric microorganisms by applying real-time PCR. As a result, nucleic acids of bacterial microorganisms were most frequently detected, followed by protozoa, microsporidia, and helminths. Interestingly, the cluster assessment confirmed interaction patterns known from the previous analysis with Colombian indigenous people, demonstrating a high likelihood of Blastocystis hominis for clustering with other microorganisms and a prominent, potentially mediating role of Dientamoeba fragilis for microbial interactions within the clusters. In conclusion, the assessment confirmed conserved clustering of enteric microorganisms with potential etiological relevance for human infectious gastroenteritis over geographically distinct high-endemicity settings. Furthermore, the composition of abundant microorganisms is more important than regional factors for the determination of the interplay of enteric microorganisms in the human gut. Thereby, some microbial pathogens and commensals seem more susceptible to a changing microbial composition in the human gut than others.

Medical complications during pregnancy have been frequently reported from Western Africa with a particular importance of infectious complications. Placental tissue can either become the target of infectious agents itself, such as, e.g., in the case of urogenital schistosomiasis, or be subjected to contamination with colonizing or infection-associated microorganisms of the cervix or the vagina during vaginal delivery. In the retrospective cross-sectional assessment presented here, the quantitative dimension of infection or colonization with selected resistant or pathogenic bacteria and parasites was regionally assessed. To do so, 274 collected placental tissues from Ivory Coastal and Ghanaian women were subjected to selective growth of resistant bacteria, as well as to molecular screening for beta-lactamase genes, Schistosoma spp. and selected bacterial causative agents of sexually transmitted infections (STI). Panton-Valentine-negative methicillin-resistant Staphylococcus aureus (MRSA) was grown from 1.8% of the tissue samples, comprising the spa types t008 and t688, as well as the newly detected ones, t12101 (n = 2) and t12102. While the culture-based recovery of resistant Enterobacterales and nonfermentative rod-shaped Gram-negative bacteria failed, molecular assessments confirmed beta-lactamase genes in 31.0% of the samples with multiple detections of up to four resistance genes per sample and bla CTX-M , bla IMP , bla GES , bla VIM , bla OXA-58 -like, bla NDM , bla OXA-23 -like, bla OXA-48 -like and bla KPC occurring in descending order of frequency. The beta-lactamase genes bla OXA-40/24 -like, bla NMC&#95;A/IMI , bla BIC , bla SME , bla GIM and bla DIM were not detected. DNA of the urogenital schistosomiasis-associated Schistosoma haematobium complex was recorded in 18.6% of the samples, but only a single positive signal for S. mansoni with a high cycle-threshold value in real-time PCR was found. Of note, higher rates of schistosomiasis were observed in Ghana (54.9% vs. 10.3% in Ivory Coast) and Cesarean section was much more frequent in schistosomiasis patients (61.9% vs. 14.8% in women without Schistosoma spp. DNA in the placenta). Nucleic acid sequences of nonlymphogranuloma-venereum-associated Chlamydia trachomatis and of Neisseria gonorrhoeae were recorded in 1.1% and 1.9% of the samples, respectively, while molecular attempts to diagnose Treponema pallidum and Mycoplasma genitalium did not lead to positive results. Molecular detection of Schistosoma spp. or STI-associated pathogens was only exceptionally associated with multiple resistance gene detections in the same sample, suggesting epidemiological distinctness. In conclusion, the assessment confirmed considerable prevalence of urogenital schistosomiasis and resistant bacterial colonization, as well as a regionally expected abundance of STI-associated pathogens. Continuous screening offers seem advisable to minimize the risks for the pregnant women and their newborns.

Competing Interests: We declare that no competing interests.

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., (© 2022. The Author(s).)

Background: Despite the introduction of efficacious interventions for malaria control, sub-Saharan Africa continues to bear the highest burden of malaria and its associated effects on vulnerable populations, such as pregnant women and children. This meta-ethnographic review contributes to literature on malaria in pregnancy interventions in sub-Saharan Africa by offering insights into the multiple factors that motivate or demotivate women from accessing MiP interventions., Methods: A meta-ethnographic approach was used for the synthesis. Original qualitative research articles published from 2010 to November 2021 in English in sub-Saharan Africa were searched for. Articles focusing on WHO's recommended interventions such as intermittent preventive treatment with sulfadoxine-pyrimethamine, long-lasting insecticidal nets and testing and treatment of Malaria in Pregnancy (MiP) were included. Selected articles were uploaded into Nvivo 11 for thematic coding and synthesis., Results: Twenty-seven original qualitative research articles were included in the analysis. Main factors motivating uptake of MiP interventions were: (1) well organized ANC, positive attitudes of health workers and availability of MiP services; (2) Women's knowledge of the effects of malaria in pregnancy, previous experience of accessing responsive ANC; (3) financial resources and encouragement from partners, relatives and friends and (4) favourable weather condition and nearness to a health facility. Factors that demotivated women from using MiP services were: (1) stock-outs, ANC charges and health providers failure to provide women with ample education on the need for MiP care; (2) perception of not being at risk and the culture of self-medication; (3) fear of being bewitched if pregnancy was noticed early, women's lack of decision-making power and dependence on traditional remedies and (4) warm weather, long distances to health facilities and the style of construction of houses making it difficult to hang LLINs., Conclusions: Health system gaps need to be strengthened in order to ensure that MiP interventions become accessible to women. Additionally, health managers need to involve communities in planning, designing and implementing malaria interventions for pregnant women. It is important that the health system engage extensively with communities to facilitate pregnant women and communities understanding of MiP interventions and the need to support pregnant women to access them., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Background: There has been a global decline in malaria transmission over the past decade. However, not much is known of the impact of this observation on the burden of malaria infection in pregnancy in endemic regions including Ghana. A narrative review was undertaken to help describe trends in malaria infection in pregnancy in Ghana. Among others, such information is important in showing any progress made in malaria in pregnancy control., Methods: To describe trends in pregnancy-associated malaria infection in Ghana, a search and review of literature reporting data on the prevalence of asymptomatic Plasmodium falciparum infection in pregnancy was conducted., Results: Thirty-six (36) studies, conducted over 1994-2019, were included in the review. In the northern savannah zone with largely seasonal malaria transmission, prevalence appeared to reduce from about 50-60% in 1994-2010 to 13-26% by 2019. In the middle transitional/forest zone, where transmission is perennial with peaks in the rainy season, prevalence apparently reduced from 60% in the late 1990 s to about 5-20% by 2018. In the coastal savannah area, there was apparent reduction from 28 to 35% in 2003-2010 to 5-11% by 2018-2019. The burden of malaria infection in pregnancy continues to be highest among teenagers and younger-aged pregnant women and paucigravidae., Conclusions: There appears to be a decline in asymptomatic parasite prevalence in pregnancy in Ghana though this has not been uniform across the different transmission zones. The greatest declines were noticeably in urban settings. Submicroscopic parasitaemia remains a challenge for control efforts. Further studies are needed to evaluate the impact of the reduced parasite prevalence on maternal anaemia and low birthweight and to assess the local burden of submicroscopic parasitaemia in relation to pregnancy outcomes., (© 2021. The Author(s).)

Background: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections., Methods: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789., Findings: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I 2 =67.0 %) and patent infection (RR=1.02, 0.61-1.16, I 2 =0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I 2 =0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I 2 =54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57)., Interpretation: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections., Funding: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network., Competing Interests: All authors declare no competing interests.

Background: Intermittent preventive treatment of malaria among pregnant women with sulfadoxine-pyrimethamine (IPTp-SP), is one of the three recommended interventions for the prevention of malaria in pregnancy (MiP) in sub-Sahara Africa. The World Health Organisation recommended in 2012 that SP be given at each scheduled ANC visit except during the first trimester and can be given a dose every month until the time of delivery, to ensure that a high proportion of women receive at least three doses of SP during pregnancy. Despite implementation of this policy, Ghana did not attain the target of 100% access to IPTp-SP by 2015. Additionally, negative outcomes of malaria infection in pregnancy are still recurring. This ethnographic study explored how health system, individual and socio-cultural factors influence IPTp-SP uptake in two Ghanaian regions., Methods: The study design was ethnographic, employing non-participant observation, case studies and in depth interviews in 8 health facilities and 8 communities, from April 2018 to March 2019, in two Ghanaian regions. Recommended ethical procedures were observed., Results: Health system factors such as organization of antenatal care (ANC) services and strategies employed by health workers to administer SP contributed to initial uptake. Women's trust in the health care system contributed to continued uptake. Inadequate information provided to women accessing ANC, stock-outs and fees charged for ANC services reduced access to IPTp-SP. Socio-cultural factor such as encouragement from social networks influenced utilization of ANC services and IPTp-SP uptake. Individual factors such as refusing to take SP, skipping ANC appointments and initiating ANC attendance late affected uptake., Conclusion: Health system, socio-cultural and individual factors influence uptake of optimum doses of IPTp-SP. Consequently, interventions that aim at addressing IPTp-SP uptake should focus on regular and sufficient supply of SP to health facilities, effective implementation of free ANC, provision of appropriate and adequate information to women and community outreach programmes to encourage early and regular ANC visits., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Malaria interventions including use of Sulfadoxine-Pyrimethamine as Intermittent Preventive Treatment (IPTp-SP) and distribution of Insecticide Treated Nets (ITNs) have been implemented through ante-natal clinic (ANC) services in Ghana. Yet, the high ANC attendance is not commensurate with the uptake of these interventions, with missed opportunities to deliver the interventions. This study sought to assess the health system factors affecting access and delivery of IPTp-SP and ITN as defined by the Ghana Malaria Policy Guideline to eligible pregnant women attending ANC clinic sessions., Methods: A quantitative cross-sectional study was conducted in the Volta Region of Ghana, with data collected across three levels of health care delivery facilities, including hospitals, health centres and Community-Based Health Planning Service (CHPS) compounds. Data collection included structured observation checklists to document the communication and interaction between the ANC health staff and pregnant women. Additionally, structured questionnaires were used to elicit information on cadre, trainings attended, knowledge and delivery practices of health workers on IPTp-SP and ITN. Stata 16 was used for data analysis, and a defined delivery algorithm was used to compute appropriate and inappropriate delivery practices, using the Ghana policy directive as a guide. Predictors of appropriate delivery were determined using logistic regression analysis., Results: Approximately 97% of the 680 ANC observations had complete information for analysis. Of these, 78% (511/657) were eligible for IPTp-SP after excluding women who have less than 16 weeks of gestation, G6PD deficient, malaria positive and have taken 5 doses of IPTp-SP prior to day of observation. Appropriate delivery of IPTp-SP was 76% (390/511). Despite the availability of SP, 15% (75/511) of all eligible women were not offered the medication and 37% (44/119) of inappropriate delivery was recorded during periods of stock out. ITNs were appropriately delivered to 59% (139) out of 237 eligible women. Thirty-two percent (77/237) of eligible women, mostly continuing ANC clients, were not given ITN despite stock availability., Conclusions: IPTp-SP was appropriately delivered to most of the eligible pregnant women compared to ITN. While stock out of both intervention could account for inappropriate delivery, despite stock availability, IPTp-SP and ITN were not delivered to some eligible women., (© 2021. The Author(s).)

Background: Malaria in pregnancy (MiP) is an important public health problem across sub-Saharan Africa. The package of measures for its control in Ghana in the last 20 years include regular use of long-lasting insecticide-treated bed nets (LLINs), directly-observed administration (DOT) of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and prompt and effective case management of MiP. Unfortunately, Ghana like other sub-Saharan African countries did not achieve the reset Abuja targets of 100% of pregnant women having access to IPTp and 100% using LLINs by 2015., Methods: This ethnographic study explored how healthcare managers dealt with existing MiP policy implementation challenges and the consequences on IPTp-SP uptake and access to maternal healthcare. The study collected date using non-participant observations, conversations, in-depth interviews and case studies in eight health facilities and 12 communities for 12 months in two Administrative regions in Ghana., Results: Healthcare managers addressed frequent stock-outs of malaria programme drugs and supplies from the National Malaria Control Programme and delayed reimbursement from the NHIS, by instituting co-payment, rationing and prescribing drugs for women to buy from private pharmacies. This ensured that facilities had funds to pay creditors, purchase drugs and supplies for health service delivery. However, it affected their ability to enforce DOT and to monitor adherence to treatment. Women who could afford maternal healthcare and MiP services and those who had previously benefitted from such services were happy to access uninterrupted services. Women who could not maternal healthcare services resorted to visiting other sources of health care, delaying ANC and skipping scheduled ANC visits. Consequently, some clients did not receive the recommended 5 + doses of SP, others did not obtain LLINs early and some did not obtain treatment for MiP. Healthcare providers felt frustrated whenever they could not provide comprehensive care to women who could not afford comprehensive maternal and MiP care., Conclusion: For Ghana to achieve her goal of controlling MiP, the Ministry of Health and other supporting institutions need to ensure prompt reimbursement of funds, regular supply of programme drugs and medical supplies to public, faith-based and private health facilities.

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.

Background: Anaemia and malaria are both major contributors to maternal and child mortality, and morbidity, with some of the worst outcomes occurring in sub-Saharan Africa. Point of care tests (POCT), if used appropriately, provide a simple, inexpensive form of diagnostic testing, as a reliable alternative when laboratory tests are not readily available. In such resource limited settings, clinical staff tend to rely on symptom-based diagnosis and presumptive treatment. This study uses qualitative methods to identify the current practice of POCT use for malaria and anaemia, to explore the enablers and barriers to effective implementation of these POCT, and to determine how relationships between each of the stakeholder groups may impact on POCT use., Methods: Staff (clinical and laboratory) and patients (pregnant women) at three antenatal care facilities within the Ashanti Region of Ghana participated in interviews and focus group discussions (FGDs). An initial coding framework was developed based on the pre-defined objectives of the study. Thematic analysis was used to identify subthemes and categories within each of the key themes., Results: At the time data were collected all three facilities used malaria POCT either as an adjunct to microscopy, or as their only form of malaria testing. Although all three facilities were familiar with haemoglobin colour scale (HCS), none of the facilities used them routinely. Clinical staff perceived symptom-based diagnosis was a quick way to diagnosis because access to POCT during consultations was unreliable, but recognized disadvantages associated with symptom-based diagnosis. Perceived advantages of malaria and anaemia POCT were user-friendliness, improved diagnosis and opportunity for patient engagement, as well as lower cost implication for patients. Perceived disadvantages included likelihood of missed diagnosis of mild anaemia, as well as likelihood of human error leading to in accurate diagnosis which could impact on patient trust. Poor communication and lack of trust between staff groups was also identified as a barrier to effective uptake of POCT., Conclusions: Consistent supply of POCT as well as staff training and staff and patient engagement, are fundamental to successful uptake of POCT for effective malaria and anaemia management.

Background: Improving maternal health remains a priority to the Ghanaian government. Consequently, it has implemented the World Health Organization recommendation of distributing free long-lasting insecticidal nets (LLINs) to pregnant women-one of the effective strategies to combating malaria in pregnancy. However, the burden of negative outcomes of malaria in pregnancy such as low birth weight and miscarriages is still high. This may be related to the health system, socio-cultural and economic dynamics that influence LLIN use, but their role is not well understood. This ethnographic study sought to understand health system, socio-cultural, economic and environmental dynamics in utilization of LLINs among pregnant women in two Ghanaian regions., Methods: An ethnographic study design was used. In-depth interviews and conversations were conducted among health workers, pregnant women and opinion leaders. Observations were conducted in 12 communities and eight health facilities. Ethical clearance was obtained from the University of Health and Allied Sciences' Research Ethics Committee. Nvivo 11 was used to support data coding. Data were triangulated and analysed using a thematic approach., Results: Findings suggest health system, socio-cultural, economic, environmental and individual factors influenced LLIN use. Health facility readiness in stocking LLINs influenced ownership and use. Receiving appropriate information from health providers and encouragement from public officials improved LLIN use. Women with a history of LLIN use prior to becoming pregnant and women who had young children remained consistent users. Experiencing irritating effects of LLINs and preference for traditional methods to wade off mosquitoes, reduced LLIN use. Pregnant women whose household and family members used LLINs were influenced positively to use them. Gender power relations between husbands and wives influenced women's use of LLINs. The type of housing and weather conditions contributed to inconsistent use. Staying out late for business purposes and to converse, exposed pregnant women to mosquito bites., Conclusion: Giving out LLINs at facility level should be accompanied with comprehensive information, which is relevant to the socio-cultural context that women live in. Mass distribution should factor in individual and public information to promote community acceptance and proper use of ITNs. Facilities should be encouraged to constantly maintain LLINs stock in order to ensure that ANC registrants receive LLINs for use.

Ghanaian children (2176) aged <5 years who presented with undifferentiated acute respiratory distress were tested for respiratory pathogens using a BioFire FilmArray polymerase chain reaction assay. Rhinovirus and/or enterovirus was detected in 36% of the assays, respiratory syncytial virus in 11%, and parainfluenza in 7%. Respiratory syncytial virus and metapneumovirus were detected more frequently in the rainy season than in the dry season., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant's health., Methods: Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin-piperaquine (DHA-PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday., Results: Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found., Conclusions: Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings. Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423.

Background: Determining gestational age in resource-poor settings is challenging because of limited availability of ultrasound technology and late first presentation to antenatal clinic. Last menstrual period (LMP), symphysio-pubis fundal height (SFH) and Ballard Score (BS) at delivery are therefore often used. We assessed the accuracy of LMP, SFH, and BS to estimate gestational age at delivery and preterm birth compared to ultrasound (US) using a large dataset derived from a randomized controlled trial in pregnant malaria patients in four African countries., Methods: Mean and median gestational age for US, LMP, SFH and BS were calculated for the entire study population and stratified by country. Correlation coefficients were calculated using Pearson's rho, and Bland Altman plots were used to calculate mean differences in findings with 95% limit of agreements. Sensitivity, specificity, positive predictive value and negative predictive value were calculated considering US as reference method to identify term and preterm babies., Results: A total of 1630 women with P. falciparum infection and a gestational age > 24 weeks determined by ultrasound at enrolment were included in the analysis. The mean gestational age at delivery using US was 38.7 weeks (95%CI: 38.6-38.8), by LMP, 38.4 weeks (95%CI: 38.0-38.9), by SFH, 38.3 weeks (95%CI: 38.2-38.5), and by BS 38.0 weeks (95%CI: 37.9-38.1) (p < 0.001). Correlation between US and any of the other three methods was poor to moderate. Sensitivity and specificity to determine prematurity were 0.63 (95%CI 0.50-0.75) and 0.72 (95%CI, 0.66-0.76) for LMP, 0.80 (95%CI 0.74-0.85) and 0.74 (95%CI 0.72-0.76) for SFH and 0.42 (95%CI 0.35-0.49) and 0.77 (95%CI 0.74-0.79) for BS., Conclusions: In settings with limited access to ultrasound, and in women who had been treated with P. falciparum malaria, SFH may be the most useful antenatal tool to date a pregnancy when women present first in second and third trimester. The Ballard postnatal maturation assessment has a limited role and lacks precision. Improving ultrasound facilities and skills, and early attendance, together with the development of new technologies such as automated image analysis and new postnatal methods to assess gestational age, are essential for the study and management of preterm birth in low-income settings.

Background: The burden of malaria and anaemia in pregnancy remains high despite the availability of proven efficacious antenatal care interventions. Sub-optimal uptake of the interventions may be due to inadequate active participation of pregnant women in their antenatal care. It was hypothesized that providing opportunities for pregnant women to improve upon active participation in their antenatal care through malaria and anaemia point-of-care testing would improve adherence to ANC recommendations and interventions and lead to better pregnancy outcomes., Methods: Fourteen antenatal clinics in the Ashanti region of Ghana were randomized into intervention (pregnant women participating in their care plus current routine care) and control (current routine care) arms. Pregnant women attending the clinics for the first time were recruited and followed up until delivery. Haemoglobin levels and malaria parasitaemia were measured at baseline, 4-8 weeks after recruitment and at 36-40 weeks gestation. Birth weight and pregnancy outcomes were also recorded., Results: The overall mean age, gestational age and haemoglobin at baseline were 26.4 years, 17.3 weeks and 110 g/l, respectively, with no significant differences between groups; 10.7% had asymptomatic parasitaemia; 74.6% owned an ITN but only 48.8% slept under it the night before enrolment. The adjusted risk ratio by 8 weeks follow up and at 36-40 weeks gestation in the intervention versus the control was 0.97 (95% CI 0.78-1.22) and 0.92 (95% CI 0.63-1.34) for anaemia and 1.17 (95% CI 0.68-2.04) and 0.83 (95% CI 0.27-2.57) for parasitaemia. The adjusted risk ratio for low birth weight was 0.93 (95% CI 0.44-1.97) and for pregnancy complications (abortions, intrauterine fetal deaths and still births) was 0.77 (95% CI 0.17-3.52) in the intervention group versus controls., Conclusion: Although its potential was evident, this study found no significant beneficial effect of women participating in their malaria and haemoglobin tests on pregnancy outcomes. Exploring factors influencing health worker compliance to health intervention implementation and patient adherence to health interventions within this context will contribute in future to improving intervention effectiveness. Trial registration ISRTCTN88917252.

Data on prevalence of antimalarial molecular resistance markers in pregnant women in Ghana is scarce. Prevalence of single nucleotide polymorphisms/haplotypes in the Pfcrt , Pfmdr1 , Pfdhfr , and Pfdhps genes was assessed in a cross-sectional study involving 200 pregnant women. Almost 90% of infections were wild type at the Pfcrt gene whereas the Pfmdr1 NFD mutant haplotype occurred in 43% of samples. Prevalence of Pfdhfr/Pfdhps quadruple mutation was 92.6% whereas Pfdfr/Pfdhps quintuple mutation with K540E was not observed. The study provides important updates of antimalarial resistance markers in Ghanaian pregnant women and suggests increased tolerance to one of the first-line treatment options in Ghana: artemether-lumefantrine. The data support the view that sulfadoxine-pyrimethamine is still efficacious for intermittent preventive treatment in Ghana, but the impact of increased doses on selection of mutations needs to be assessed. Continuing the surveillance of resistance markers is important to inform changes in antimalarial drug policy in pregnancy.

Substantial progress has been made in the control of malaria in Africa but much remains to be done before malaria elimination on the continent can be achieved. Further progress can be made by enhancing uptake of existing control tools but, in high transmission areas, additional tools will be needed. Development and evaluation of these new tools will require a substantial cadre of African scientists well trained in many different disciplines. This paper describes the activities undertaken by the Malaria Capacity Development Consortium (MCDC) to support the careers of PhD students and postdoctoral fellows undertaking research on malaria at five African universities. A systematic assessment of constraints on PhD training and research support systems was undertaken at each partner African university at the beginning of the programme and many of these constraints were remedied. The success of the programme is shown by the fact that 18 of the 21 PhD students recruited to the programme completed their theses successfully within a 4-year period and that all 27 scientists recruited to the postdoctoral programme were still working in Africa on its completion. The work of the consortium will be continued through Career Development Groups established at each partner university and at an affiliated institution at the University of Nairobi and through the Developing Excellence in Leadership, Training and Science award from the Wellcome Trust made to one of the African partners. Lessons learnt during the MCDC programme may help the planning and execution of other research capacity development programmes in Africa., Competing Interests: Competing interests: None declared.

In malaria-endemic areas, Plasmodium falciparum prevalence is often high in young women because of 1) low use of insecticide-treated nets before their first pregnancy and 2) acquired immunity, meaning infections are asymptomatic and thus untreated. Consequently, a common source of malaria in pregnancy (MiP) may be infected women becoming pregnant, rather than pregnant women becoming infected. In this study, prevalence of infection was determined by microscopy at first antenatal care (ANC) visit in primigravidae and secundigravidae in Ghana, Burkina Faso, Mali, and The Gambia, four countries with strong seasonal variations in transmission. Duration of pregnancy spent in the rainy season and other risk factors for infection were evaluated using multivariable Poisson regression. We found that the overall prevalence of malaria at first ANC was generally high and increased with time spent pregnant during the rainy season: prevalence among those with the longest exposure was 59.7% in Ghana, 56.7% in Burkina Faso, 42.2% in Mali, and 16.8% in Gambia. However, the prevalence was substantial even among women whose entire pregnancy before first ANC had occurred in the dry season: 41.3%, 34.4%, 11.5%, and 7.8%, respectively, in the four countries. In multivariable analysis, risk of infection was also higher among primigravidae, younger women, and those of lower socioeconomic status, independent of seasonality. High prevalence among women without exposure to high transmission during their pregnancy suggests that part of the MiP burden results from long-duration infections, including those acquired preconception. Prevention of malaria before pregnancy is needed to reduce the MiP burden.

Objectives: Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps., Setting: Four African universities., Participants: 83 university staff and students from 11 cadres., Intervention/methods: A literature-informed 'benchmark' was developed and used to itemise all components of a university's health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified., Results: Common gaps in operational health research capacity included no accessible research strategy, a lack of research e-tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges., Conclusions: Identification of each institutions' strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a 'smart' investment for governments and health research funders., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To determine whether dihydroartemisinin-piperaquine (DHA-PPQ) is non-inferior to artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria infection in pregnancy., Methods: A total of 417 second/ third trimester pregnant women with confirmed asymptomatic Plasmodium falciparum parasitaemia were randomised to receive DHA-PPQ or ASAQ over 3 days. Women were followed up on days 1, 2, 3, 7, 14, 28 and 42 after treatment start and at delivery for parasitological, haematological, birth outcomes and at 6-week post-partum to ascertain the health status of the babies. Parasitological efficacy (PE) by days 28 and 42 were co-primary outcomes. Analysis was per-protocol (PP) and modified intention-to-treat (ITT). Non-inferiority was declared if the two-sided 95% confidence interval for PE at the endpoints excluded 5% lower efficacy for DHA-PPQ. Secondary outcomes were assessed for superiority., Results: In PP analysis, PE was 91.6% for DHA-PPQ and 89.3% for ASAQ by day 28 and 89.0% and 86.5%, respectively, by day 42. DHA-PPQ was non-inferior to ASAQ with respect to uncorrected PE [adjusted difference by day 28 (DHA-PPQ-ASAQ); 3.5% (95%CI: -1.5, 8.5); and day 42: 3.9% (95%CI: -2.7, 10.4)]. ITT analysis gave similar results. PCR to distinguish recrudescence and reinfection was unsuccessful. DHA-PPQ recipients had fewer adverse events of vomiting, dizziness, and general weakness compared to ASAQ. Both drugs were well-tolerated, and there was no excess of adverse birth outcomes., Conclusion: DHA-PPQ was non-inferior to ASAQ for treatment of malaria infection during pregnancy. No safety concerns were identified. Our findings contribute to growing evidence that DHA-PPQ is useful for control of malaria in pregnancy., (© 2017 John Wiley & Sons Ltd.)

Background: In low-income and middle-income countries, invasive mechanical ventilation is often not available for children at risk of death from respiratory failure. We aimed to determine if continuous positive airway pressure (CPAP), a form of non-invasive ventilation, decreases all-cause mortality in children with undifferentiated respiratory distress in Ghana., Methods: This open-label, cluster, crossover trial was done in two Ghanaian non-tertiary hospitals where invasive mechanical ventilation is not routinely available. Eligible participants were children aged from 1 month to 5 years with a respiratory rate of more than 50 breaths per min in children 1-12 months old, or more than 40 breaths per min in children older than 12 months, and use of accessory muscles or nasal flaring. CPAP machines were allocated to one hospital during each study block, while the other hospital served as the control site. The initial intervention site was randomly chosen using a coin toss. 5 cm of water pressure was delivered via CPAP nasal prongs. The primary outcome measure was all-cause mortality rate at 2 weeks after enrolment in patients for whom data were available after 2 weeks. We also did post-hoc regression analysis and subgroup analysis of children by malaria status, oxygen saturation, and age. This study is registered with ClinicalTrials.gov, number NCT01839474., Findings: Between Jan 20, 2014, and Dec 5, 2015, 2200 children were enrolled: 1025 at the intervention site and 1175 at the control site. Final analysis included 1021 patients in the CPAP group and 1160 patients in the control group. 2 weeks after enrolment, 26 (3%) of 1021 patients in the CPAP group, and 44 (4%) of 1160 patients in the control group, had died (relative risk [RR] of mortality 0·67, 95% CI 0·42-1·08; p=0·11). In children younger than 1 year, all-cause mortality was ten (3%) of 374 patients in the CPAP group, and 24 (7%) of 359 patients in the control group (RR 0·40, 0·19-0·82; p=0·01). After adjustment for study site, time, and clinically important variables, the odds ratio for 2-week mortality in the CPAP group versus the control group was 0·4 in children aged up to 6 months, 0·5 for children aged 12 months, 0·7 for children aged 24 months, and 1·0 for those aged 36 months. 28 patients (3%) in the CPAP group and 24 patients (2%) in the control group had CPAP-related adverse events, such as vomiting, aspiration, and nasal, skin, or eye trauma. No serious adverse events were observed., Interpretation: In the unadjusted analysis the use of CPAP did not decrease all-cause 2-week mortality in children 1 month to 5 years of age with undifferentiated respiratory distress. After adjustment for study site, time, and clinically important variables, 2-week mortality in the CPAP group versus the control group was significantly decreased in children 1 year of age and younger. CPAP is safe and improves respiratory rate in a non-tertiary setting in a lower-middle-income country., Funding: General Electric Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Seasonal Malaria Chemoprevention (SMC) is currently recommended for children under five in areas where malaria transmission is highly seasonal. We explored children's caregivers' and community health workers' (CHWs) responses to an extended 5-month SMC programme., Methods: Thirteen in-depth interviews and eight focus group discussions explored optimal and suboptimal 'uptake' of SMC to examine facilitators and barriers to caregivers' uptake., Results: There did not appear to be major differences between caregivers of children with optimal and sub-optimal SMC uptake in terms of their knowledge of malaria, their perceptions of the effect of SMC on a child's health, nor their understanding of chemoprevention. Caregivers experienced difficulty in prioritising SMC for well children, perceiving medication being for treatment rather than prevention. Prior to the study, caregivers had become accustomed to rapid diagnostic testing (RDT) for malaria, and therefore blood testing for malaria during the baseline survey at the start of the SMC programme may have positively influenced uptake. Facilitators of uptake included caregivers' trust in and respect for administrators of SMC (including CHWs), access to medication and supportive (family) networks. Barriers to uptake related to poor communication of timings of community gatherings, travel distances, absence during SMC home deliveries, and limited demand for SMC due to lack of previous experience. Future delivery of SMC by trained CHWs would be acceptable to caregivers., Conclusion: A combination of caregivers' physical access to SMC medication, the drug regimen, trust in the medical profession and perceived norms around malaria prevention all likely influenced caregivers' level of uptake. SMC programmes need to consider: 1) developing supportive, accessible and flexible modes of drug administration including home delivery and village community kiosks; 2) improving demand for preventive medication including the harnessing of learnt trust; and 3) developing community-based networks for users to support optimal uptake of SMC., Competing Interests: The authors have declared that no competing interests exist.

Background: Emergence of high-grade sulfadoxine-pyrimethamine (SP) resistance in parts of Africa has led to growing concerns about the efficacy of intermittent preventive treatment of malaria during pregnancy (IPTp) with SP. The incremental cost-effectiveness of intermittent screening and treatment (ISTp) with artemether-lumefantrine (AL) as an alternative strategy to IPTp-SP was estimated followed by a simulation of the effects on cost-effectiveness of decreasing efficacy of IPTp-SP due to SP resistance. The analysis was based on results from a multi-centre, non-inferiority trial conducted in West Africa., Methods: A decision tree model was analysed from a health provider perspective. Model parameters for all trial countries with appropriate ranges and distributions were used in a probabilistic sensitivity analysis. Simulations were performed in hypothetical cohorts of 1000 pregnant women who received either ISTp-AL or IPTp-SP. In addition a cost-consequences analysis was conducted. Trial estimates were used to calculate disability-adjusted-life-years (DALYs) for low birth weight and severe/moderate anaemia (both shown to be non-inferior for ISTp-AL) and clinical malaria (inferior for ISTp-AL). Cost estimates were obtained from observational studies, health facility costings and public procurement databases. Results were calculated as incremental cost per DALY averted. Finally, the cost-effectiveness changes with decreasing SP efficacy were explored by simulation., Results: Relative to IPTp-SP, delivering ISTp-AL to 1000 pregnant women cost US$ 4966.25 more (95 % CI US$ 3703.53; 6376.83) and led to a small excess of 28.36 DALYs (95 % CI -75.78; 134.18), with LBW contributing 81.3 % of this difference. The incremental cost-effectiveness ratio was -175.12 (95 % CI -1166.29; 1267.71) US$/DALY averted. Simulations show that cost-effectiveness of ISTp-AL increases as the efficacy of IPTp-SP decreases, though the specific threshold at which ISTp-AL becomes cost-effective depends on assumptions about the contribution of bed nets to malaria control, bed net coverage and the willingness-to-pay threshold used., Conclusions: At SP efficacy levels currently observed in the trial settings it would not be cost-effective to switch from IPTp-SP to ISTp-AL, mainly due to the substantially higher costs of ISTp-AL and limited difference in outcomes. The modelling results indicate thresholds below which IPT-SP efficacy must fall for ISTp-AL to become a cost-effective option for the prevention of malaria in pregnancy.

Background: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa., Methods: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes., Results: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups)., Conclusions: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Background: Little is known about the course of perinatal anxiety, particularly in low and middle income countries. This study aimed at examining trajectories of ante- and postpartum generalized anxiety symptoms in West-African women and their associations with mother and child characteristics., Methods: 778 women from Côte d'Ivoire and Ghana were investigated between 04/2010 and 03/2014. Anxiety symptoms were measured using the seven-item Generalized Anxiety Disorder scale (GAD-7) at three months antepartum and three, 12 and 24 months postpartum. Growth mixture modeling was applied to identify latent trajectory classes of anxiety. Multinomial logistic regression was used to investigate the associations of psychosocial, sociodemographic, obstetric and clinical characteristics with different trajectories., Results: Four distinct trajectories of anxiety were identified. The majority of women (79.8%) had consistent low anxiety symptoms, while 11.4% had elevated anxiety scores before and around childbirth that decreased gradually. 5.4% of women showed increasing anxiety symptoms over time. Few women (3.3%) had transient anxiety with elevated scores at three and 12 months postpartum. Risk factors for elevated anxiety levels around childbirth were antepartum depressive symptoms, higher levels of stress (economic, marital and social stress), lower child birth weight, and multiparity. Partner support was found to be protective., Limitations: Anxiety symptoms were assessed using a screening instrument and not through a formal diagnostic classification system. Some putative risk factors were not investigated, and some psychosocial factors were assessed retrospectively., Conclusion: The presence of different trajectories underline the importance of monitoring anxiety symptoms in pregnant women and in mothers with infants/toddlers., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Intermittent screening and treatment in pregnancy (ISTp) is a potential strategy for the control of malaria during pregnancy. However, the frequency and consequences of malaria infections missed by a rapid diagnostic test (RDT) for malaria are a concern., Methods: Primigravidae and secundigravidae who participated in the ISTp arm of a noninferiority trial in 4 West African countries were screened with an HRP2/pLDH RDT on enrollment and, in Ghana, at subsequent antenatal clinic (ANC) visits. Blood samples were examined subsequently by microscopy and by a polymerase chain reaction (PCR) assay., Results: The sensitivity of the RDT to detect peripheral blood infections confirmed by microscopy and/or PCR at enrollment ranged from 91% (95% confidence interval [CI], 88%, 94%) in Burkina Faso to 59% (95% CI, 48%, 70% in The Gambia. In Ghana, RDT sensitivity was 89% (95% CI, 85%, 92%), 83% (95% CI, 76%, 90%) and 77% (95% CI, 67%, 86%) at enrollment, second and third ANC visits respectively but only 49% (95% CI, 31%, 66%) at delivery. Screening at enrollment detected 56% of all infections detected throughout pregnancy. Seventy-five RDT negative PCR or microscopy positive infections were detected in 540 women; these were not associated with maternal anemia, placental malaria, or low birth weight., Conclusions: The sensitivity of an RDT to detect malaria in primigravidae and secundigravidae was high at enrollment in 3 of 4 countries and, in Ghana, at subsequent ANC visits. In Ghana, RDT negative malaria infections were not associated with adverse birth outcomes but missed infections were uncommon., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Rapid rural-urban migration of people to cities is a reality around the globe that has increased city slum dwellers. Sodom and Gomorrah is a city slum located in the heart of Accra, Ghana. Like other slums, it lacks basic amenities necessary for dwellers' quality of life. This study describes residents' access to health and factors associated with the use of healthcarefacilities., Methods: Questionnaires were administered in systematically selected shacks across the entire slum. Data on demographic characteristics, existent health facilities and number of users, health-insured residents and knowledge of common diseases were collected., Results: Majority of the residents were from the northern parts of Ghana, relative to the south and a few of them come from other parts of West Africa. Seventy-one percent of residents had never visited a health facility in the last 5 years. When necessary, they access health care from drug stores (61.1%) or hospitals (33.1%). Residents' age, educational status, income, health knowledge and membership of National Health Insurance Scheme were significantly (p &lt; 0.05) associated with the use of healthcare facilities. Younger residents and those without National Health Insurance Scheme membership, formal education, no knowledge of common illnesses and regular income were significantly less likely to use a healthcare facility. For most residents, neither distance (73.2%) nor transportation to health facilities was a problem (74.1%)., Conclusion: Conditions of profound environmental hazards, overcrowding, poor-quality housing and lack of health care in Sodom and Gomorrah pose grave threats to the health of the inhabitants. Multisectoral interventions and resource mobilisation championed by the Ministry of Local Government and Rural Development are needed to alter the trend.

Objective: To investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case management with long-acting artemisinin-based combination therapies (ACTs) for the control of malaria in areas of extended seasonal malaria transmission., Method: Individually randomised, placebo-controlled trial in the Ashanti Region of Ghana. A total of 2400 children aged 3-59 months received either: (i) a short-acting ACT for case management of malaria (artemether-lumefantrine, AL) plus placebo SMC, or (ii) a long-acting ACT (dihydroartemisinin-piperaquine, DP) for case management plus placebo SMC or (iii) AL for case management plus active SMC with sulphadoxine-pyrimethamine and amodiaquine. SMC or placebo was delivered on five occasions during the rainy season. Malaria cases were managed by community health workers, who used rapid diagnostic tests to confirm infection prior to treatment., Results: The incidence of malaria was lower in children given SMC during the rainy season. Compared to those given placebo SMC and AL for case management, the adjusted hazard ratio (aHR) was 0.62 (95% CI: 0.41, 0.93), P = 0.020 by intention to treat and 0.53 (95% CI: 0.29, 0.95), P = 0.033 among children given five SMC courses. There were no major differences between groups given different ACTs for case management (aHR DP vs. AL 1.18 (95% CI 0.83, 1.67), P = 0.356)., Conclusion: SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC schedules is needed to maximise its impact in such settings., (© 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: Non-Plasmodium falciparum malaria infections are found in many parts of sub-Saharan Africa but little is known about their importance in pregnancy., Methods: Blood samples were collected at first antenatal clinic attendance from 2526 women enrolled in a trial of intermittent screening and treatment of malaria in pregnancy (ISTp) versus intermittent preventive treatment (IPTp) conducted in Burkina Faso, The Gambia, Ghana and Mali. DNA was extracted from blood spots and tested for P. falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale using a nested PCR test. Risk factors for a non-falciparum malaria infection were investigated and the influence of these infections on the outcome of pregnancy was determined., Results: P. falciparum infection was detected frequently (overall prevalence by PCR: 38.8 %, [95 % CI 37.0, 40.8]), with a prevalence ranging from 10.8 % in The Gambia to 56.1 % in Ghana. Non-falciparum malaria infections were found only rarely (overall prevalence 1.39 % [95 % CI 1.00, 1.92]), ranging from 0.17 % in the Gambia to 3.81 % in Mali. Ten non-falciparum mono-infections and 25 mixed falciparum and non-falciparum infections were found. P. malariae was the most frequent non-falciparum infection identified; P. vivax was detected only in Mali. Only four of the non-falciparum mono-infections were detected by microscopy or rapid diagnostic test. Recruitment during the late rainy season and low socio-economic status were associated with an increased risk of non-falciparum malaria as well as falciparum malaria. The outcome of pregnancy did not differ between women with a non-falciparum malaria infection and those who were not infected with malaria at first ANC attendance., Conclusions: Non-falciparum infections were infrequent in the populations studied, rarely detected when present as a mono-infection and unlikely to have had an important impact on the outcome of pregnancy in the communities studied due to the small number of women infected with non-falciparum parasites.

Background: Several studies have reported an association between malaria infection of the placenta and the risk of malaria in young children in the first year of life, but it is not known if this is causal, or influenced by malaria control measures during pregnancy. This paper compares the incidence of malaria in infants born to mothers who received either intermittent preventive treatment with sulfadoxine/pyrimethamine (IPTp-SP) or screening with a rapid diagnostic test and treatment with artemether-lumefantrine (ISTp-AL) during their pregnancy., Methods: From July 2011 to April 2013, 988 infants of women enrolled in a trial of IPTp-SP versus ISTp-AL in the Kassena-Nankana districts of northern Ghana were followed to determine the risk of clinical malaria during early life, and their risk of parasitaemia and anaemia at 6 and 12 months of age. In addition, the incidence of clinical malaria in infants whose mothers had malaria infection of the placenta was compared with that in infants born to women free of placental malaria., Results: The incidence of clinical malaria was 0.237 and 0.211 episodes per child year in infants whose mothers had received ISTp-AL or IPTp-SP, respectively. The adjusted incidence rate ratio and the adjusted rate difference were 0.94 (95% CI 0.68, 1.33) and 0.029 (95% CI -0.053, 0.110) cases per child year at risk respectively. The incidence of clinical malaria was similar in infants born to women with placental malaria (0.195 episodes per child year) and in infants of women without placental malaria (0.224 episodes per child year) (rate ratio = 0.86 [95% CI 0.54, 1.37])., Conclusion: Infants born to women managed with ISTp-AL during pregnancy were not at greatly increased risk of malaria compared with infants born to women who had received IPTp-SP. The incidence of malaria in infants was similar whether or not their mother had had placental malaria.

Background: Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations., Discussion: Our limited analysis suggests that the sponsors definition from the 1995 WHO Good Clinical Practices code has been integrated as such into many legislations, guidelines and regulations, and that it is not adequate to cover today's reality of funding arrangements in global health, where the legal responsibility and the funding source are de facto split. In agreement with other groups, we suggest that the international Good Clinical Practices codes should be updated to reflect the reality of non-commercial clinical research. In particular, they should explicitly include the distinction between commercial and non-commercial sponsors, and provide guidance to non-commercial sponsors for negotiating with external funding agencies and other research counterparts. Non-commercial sponsors of clinical trials should surely invest in the development of adequate legal, administrative and management skills. By acknowledging their role and specificities, and by providing them with adapted guidance, the international Good Clinical Practices codes would provide valuable guidance and support to non-commercial clinical research, whose relevance for global health is increasingly evident.

Background: The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women (ISTp) is an alternative approach., Methods and Findings: An open, individually randomized, non-inferiority trial of IPTp-SP versus ISTp was conducted in 5,354 primi- or secundigravidae in four West African countries with a low prevalence of resistance to SP (The Gambia, Mali, Burkina Faso and Ghana). Women in the IPTp-SP group received SP on two or three occasions whilst women in the ISTp group were screened two or three times with a RDT and treated if positive for malaria with artemether-lumefantrine (AL). ISTp-AL was non-inferior to IPTp-SP in preventing low birth weight (LBW), anemia and placental malaria, the primary trial endpoints. The prevalence of LBW was 15.1% and 15.6% in the IPTp-SP and ISTp-AL groups respectively (OR = 1.03 [95% CI: 0.88, 1.22]). The mean hemoglobin concentration at the last clinic attendance before delivery was 10.97g/dL and 10.94g/dL in the IPTp-SP and ISTp-AL groups respectively (mean difference: -0.03 g/dL [95% CI: -0.13, +0.06]). Active malaria infection of the placenta was found in 24.5% and in 24.2% of women in the IPTp-SP and ISTp-AL groups respectively (OR = 0.95 [95% CI 0.81, 1.12]). More women in the ISTp-AL than in the IPTp-SP group presented with malaria parasitemia between routine antenatal clinics (310 vs 182 episodes, rate difference: 49.4 per 1,000 pregnancies [95% CI 30.5, 68.3], but the number of hospital admissions for malaria was similar in the two groups., Conclusions: Despite low levels of resistance to SP in the study areas, ISTp-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women receiving cotrimoxazole prophylaxis in whom SP is contraindicated., Trial Registration: ClinicalTrials.gov NCT01084213 Pan African Clinical trials Registry PACT201202000272122.

Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided., Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4-6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data., Discussion: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative '-value-' compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.