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Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Background Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. Methods and findings Between April 2014 and April 2015, we followed 421 Malawian mother–baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur–Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], −7.53 [−13.04, −2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], −8.57 [−13.09, −4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. Conclusions This mother–baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children., Andrea Weckman and co-workers study associations between children’s neurodevelopmental outcomes and malaria in pregnancy., Author summary Why was this study done? Large human cohorts have linked maternal infection during pregnancy (without congenital infection) to an increased risk for neurocognitive deficits and neuropsychiatric disease in exposed children. Excessive maternal immune activation, irrespective of pathogen, is thought to mediate this effect. Millions of pregnant women are at risk for malaria infection each year. To our knowledge, the impact of malaria during pregnancy on child neurodevelopment has not been systematically studied in a clinical setting. What did the researchers do and find? We conducted an observational cohort follow-up study nested within a larger randomized controlled trial with detailed records of malaria in pregnancy to examine the impact of malaria in pregnancy on neurocognitive development in exposed children. To our knowledge, our data provide the first indication in a clinical cohort that malaria in pregnancy may be a previously unrecognized risk factor for neurodevelopmental delay. Furthermore, the association of systemic inflammation with reduced neurocognitive scores highlights a potential mechanistic pathway through which malaria in pregnancy could be affecting fetal neurodevelopment. What do these findings mean? There are millions of children in malaria-endemic regions who are not currently meeting their developmental potential. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental delay in children exposed in utero. Our findings suggest that scaling up efforts to prevent malaria infection could be an effective strategy to protect mother–baby dyads from poor developmental outcomes. Larger trials powered to address potential residual confounding, with a longer follow-up period and more diverse neurocognitive and neuropsychiatric tests, are required to confirm and extend these findings.

Background Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. Methods A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and Results Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p Conclusions The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Background Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP recipients. Methods We measured SP-resistance allele frequencies in Malawian women participating in a trial comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped polymerase chain reaction-detected parasites using deep sequencing of SP-resistance alleles. Results Among 125 placental infections, A581G-bearing parasites were associated with reduced birth weight (mean difference [MD], 252 g; 95% confidence interval [CI], 46–457; P = .017). Relative to ISTp, IPTp-SP was associated with higher birth weights in women with wild-type parasites (MD, 116 g; 95% CI, −40 to 272; P = .142) and lower birth weights in women with A581G-bearing parasites (MD, 192 g; 95% CI, −264 to 648; P = .385) (Pinteraction = .033). Similar associations were noted on gestational age (Pinteraction = .075). Amongst only IPTp-SP recipients, relative to women who last received SP > 4 weeks before delivery, recent SP receipt was associated with lower birth weight in women with wild-type parasites (MD, 118 g; 95% CI, −376 to 139; P = .361) and higher birth weight in women with A581G-bearing parasites (MD, 783 g; 95% CI, −20 to 1586; P = .054) (Pinteraction = .005). Conclusions The effectiveness in birth weight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP. ISRCTN Registry www.isrctn.com/ISRCTN69800930.

BACKGROUND\ud Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes.\ud \ud METHODS\ud Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1 mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes.\ud \ud FINDINGS\ud Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1), to worsen birth outcomes by impeding vascular remodeling required for placental function.\ud \ud INTERPRETATION\ud Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes.\ud \ud FUNDING\ud This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies.

Purpose In all settings, a need exists for expedited pathology processing for patients with a suspected cancer diagnosis. In low- and middle-income countries (LMICs) with limited resources, processing pathology samples is particularly challenging, so the measurement of turnaround times (TATs) for pathology results is an important quality metric. We explored the pathology TAT for suspected cancer patients at Queen Elizabeth Central Hospital in Malawi to determine whether a difference exists when patients paid an out-of-pocket fee (paid for [PF] v nonpaid for [NPF]) to facilitate sample processing. Methods and Population This retrospective descriptive study included all patients with suspected cancer (N = 544) who underwent incisional and excisional biopsy in 2010 at Queen Elizabeth Central Hospital, a teaching hospital in Malawi. Data were abstracted from patient charts and administrative forms to build a database and determine the TAT for PF and NPF samples. Results The median TAT for the 544 patients was 71 days (interquartile range [IQR], 31 to 118 days). The median pathology processing time was 31 days (IQR, 15 to 52 days) and was shorter for PF versus NPF samples. The median TAT was 43 days for PF samples (IQR, 27 to 69 days) versus 101 days for NPF samples (IQR, 31 to 118 days), which was significantly different by the Wilcoxon rank sum test ( P < .01). Conclusion The TAT for pathology samples among patients with suspected cancer was longer than reported for other African countries during the study period, was longer than considered acceptable in high-income countries, and differed between PF and NPF samples.

Background Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB). Methods and findings We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04–1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20–2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy. Conclusions Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings., In this cohort study, Robyn Elphinstone and colleagues investigate if malaria infection in early pregnancy may be associated with changes in placental growth and function, as well as preterm birth., Author summary Why was this study done? Malaria infection during pregnancy has serious consequences for the mother and her unborn child. We have a poor understanding of the mechanisms by which malaria causes adverse birth outcomes, especially preterm birth (PTB), a leading cause of death in children less than 5 years of age. Efforts to date to prevent malaria in pregnant women have not been shown to reduce the risk of PTB associated with malaria infection. We conducted this study to assess if malaria infection, especially early in pregnancy, might alter important factors that control placental growth and function and determine if these lead to PTB. What did the researchers do and find? We measured levels of 10 different angiogenic, inflammatory, and/or metabolic proteins longitudinally during pregnancy in a large cohort of 1,628 Malawian women at risk of malaria infection and demonstrate that early infection with malaria is associated with changes in several key proteins that are important for healthy pregnancies. The use of ultrasound dating highlighted the contribution of early malaria infection to an increased risk of delivering preterm, previously thought to occur primarily from malaria late in pregnancy. What do these findings mean? Current interventions to prevent malaria in pregnancy are usually initiated at the first antenatal visit in the second trimester. This study demonstrates that many women are already malaria-infected at this first visit and that these early infections are sufficient to alter factors essential for the placenta to adequately support fetal growth and healthy pregnancy outcomes. These early infections increase the risk of delivering preterm, indicating that interventions to prevent malaria in pregnancy may need to be started earlier in pregnancy in order to reduce malaria-associated adverse birth outcomes.

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., Plasmodium falciparum infection in pregnancy is a major cause of adverse pregnancy outcomes. Here, the authors combine performance estimates of standard rapid diagnostic tests with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy.

In a randomised trial comparing intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine (DP) and intermittent preventive therapy against malaria in pregnancy (IPT) with sulfadoxine-pyrimethamine (SP) in Malawi, the impacts of IST-DP and IPT-SP on the development and maintenance of malaria antibody immunity were compared. Pregnant Malawian women were randomised to receive IST-DP or IPT-SP. In a nested study, paired enrolment and delivery plasma samples from 681 women were assayed for antibodies against recombinant antigens and for IgG and opsonising antibodies to antigens found on infected erythrocytes (IEs). At delivery, antibody responses did not differ between study arms. Between enrolment and delivery, antibodies to recombinant antigens decreased, whereas antibodies to IEs including opsonising antibodies remained stable. Overall, changes in antibody responses over pregnancy did not differ by treatment arm. Stratifying by gravidity, antibody to schizont extract decreased more in multigravidae receiving IST-DP than IPT-SP. There was minimal impact of treatment arm on the development and maintenance of malaria immunity. While antibodies to recombinant antigens declined between enrolment and delivery, antibodies directed against IEs tended to be more stable, suggesting longer-lasting protection.Clinical trial registration: Pa n African Clinical Trials Registry (PACTR201103000280319) 14/03/2011. URL: http://www.isrctn.com/ISRCTN69800930.

Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. L-arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that L-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of L- arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, L-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance L-arginine bioavailability as strategies to improve birth outcomes.

Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA’s ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: −267.99 g; 95% Confidence Interval [CI]: −466.43 g,−69.55 g) and higher odds of low birthweight (

Antenatal malaria screening with a rapid diagnostic test (RDT) and treatment only of women with positive RDT findings may potentially prevent low birth weight resulting from malaria. The consequences of subpatent antenatal infections below the detection limit of RDTs are incompletely understood. In Malawi, pregnant women of any gravidity status were tested at each antenatal visit for Plasmodium falciparum, using an RDT and polymerase chain reaction analysis, and were followed until delivery. Associations between antenatal infections and delivery outcomes were assessed with Poisson regression or analysis of variance. Compared with women with no detected antenatal P. falciparum infection, women with positive RDT findings delivered babies with a lower mean birth weight (2960 vs 2867 g; mean difference, -93 g [95% confidence interval {CI}, -27 to -159]; P = .006); this was not observed among women with only subpatent infections (mean birth weight, 3013 g; mean difference, 54 [95% CI, -33-140]; P = .2268). These differences were apparent early in pregnancy, during the second trimester: compared with uninfected women, women with positive RDT findings delivered babies with a lower mean birth weight (mean difference, -94 g [95% CI, -31 to -156]; P = .003), but women with subpatent infections did not (mean difference, 36 g [95% CI, -49-122]; P = .409). Subpatent antenatal P. falciparum infections were not associated with adverse delivery outcomes. The association of patent infections at enrollment with low birth weight suggests the importance of preventing P. falciparum infection early in pregnancy.

Parasites with increased resistance to sulfadoxine might undermine malaria control measures., Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance.

Purpose \ud The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria–nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists.\ud \ud Participants \ud Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015.\ud \ud Findings to date \ud Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort.\ud \ud Future plans \ud This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria–nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective.

Background\ud Malaria in pregnancy is a major cause of adverse maternal and fetal outcomes. Intermittent preventive treatment with sulfadoxine–pyrimethamine (IPTp-SP) is one of the control strategies promoted by WHO. In response to mounting resistance to SP, intermittent screening and treatment (ISTp) has been proposed as an alternative. The objective of this study was to explore the acceptability of ISTp for health workers and pregnant women.\ud \ud Methods\ud Semi-structured interviews of ten health workers and five focus group discussions of 38 women enrolled in an ongoing trial comparing IPTp-SP and ISTp with dihydroartemisinin–piperaquine (DP) were conducted at two antenatal clinics in rural Malawi. All transcripts were coded and themes were identified using a content analysis approach.\ud \ud Results\ud Amongst health workers, there were contrasting opinions on the preference of blood sampling methods, and the influence of method on reliability of diagnosis. The perceived greater effectiveness of DP compared to SP was appreciated, however concerns of user compliance with the full dose of DP in non-trial settings were raised. Despite the discomfort of repeated finger pricks, pregnant women were generally accepting of ISTp, particularly the chance for regular blood tests to check for infections and the perceived greater effectiveness with fewer side effects of DP compared to SP.\ud \ud Conclusion\ud In the trial context, pregnant women tended to prefer ISTp-DP over IPTp-SP. Health workers were also accepting of ISTp-DP as an alternative to IPTp-SP in light of increasing SP resistance. However, reliability of stock, adherence to malaria test results and user adherence to the full course of DP may present barriers to successful routine implementation. Effective communication with health workers and between health workers, pregnant women and their communities will be essential for the acceptability of focused antenatal care, including the best malaria control measures available.

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

Placental malaria causes low birth weight and neonatal mortality in malaria-endemic areas. The diagnosis of placental malaria is important for program evaluation and clinical care, but is compromised by the suboptimal performance of current diagnostics. Using placental and peripheral blood specimens collected from delivering women in Malawi, we compared estimation of the operating characteristics of microscopy, rapid diagnostic test (RDT), polymerase chain reaction, and histopathology using both a traditional contingency table and a latent class analysis (LCA) approach. The prevalence of placental malaria by histopathology was 13.8%; concordance between tests was generally poor. Relative to histopathology, RDT sensitivity was 79.5% in peripheral and 66.2% in placental blood; using LCA, RDT sensitivities increased to 93.7% and 80.2%, respectively. Our results, if replicated in other cohorts, indicate that RDT testing of peripheral or placental blood may be suitable approaches to detect placental malaria for surveillance programs, including areas where intermittent preventive therapy in pregnancy is not used.

Background\ud Risk Difference (RD) is becoming the measure of choice for estimating effect size in antimalarial drug efficacy trials. Calculating RD using binomial regression is prone to model nonconvergence. Cheung’s modified ordinary least squares (OLS) method is a proven technique for handling non-convergence when estimating RD. Other promising methods include the Poison, Additive Binomial Regression and binary regression models fitted using the statistical package R. (Deddens’) Copy method that was primarily developed to overcome non-convergence of log-binomial regression models when estimating risk ratios is another potential method. Simulations were conducted to compare the performance of the Copy method against four alternatives (Cheung’s modified OLS method, the Additive Binomial Regression Model fitted with the blm algorithm, the binary regression model fitted with the glm2 algorithm, and the Poisson model with identity link and robust standard errors fitted with the glm algorithm) for obtaining RD estimates when a binomial model fails to converge.\ud \ud Methods\ud We computed estimates of efficiency and bias with treatment arm efficacies of (a) 60% vs. 85%, (b) 95% vs. 90%, (iii) 95% vs. 98% using simulation studies. A total of 5,000 datasets were simulated under each of these three scenarios.\ud \ud Results\ud The modified OLS method and the binary regression model fitted using the glm2 algorithm in R provided unbiased, efficient estimates of RD across all assessed scenarios. In contrast, the Copy method yielded biased estimates of RD even when 100% convergence was achieved. The Poisson and Additive Binomial Regression models had 100% and almost 100% convergence rates respectively, but both produced very slightly biased RD estimates.\ud \ud Conclusion\ud The Copy method is not suitable for estimating RD when binomial regression model fitting fails to converge. Cheung’s modified OLS or the binary regression model fitted using the glm2 algorithm in R should be the method of choice to overcome non-convergence with binomial models for calculating adjusted RD estimates.

Pregnant women with influenza infection are at increased risk of developing complications compared with other adults. Information about burden of influenza in pregnant women in Africa is limited. To determine incidence and seasonality of influenza-like illness (ILI) in pregnant women in Blantyre, Malawi, we recruited a cohort of 450 pregnant women and conducted surveillance for ILI and malaria infection. We recorded gestational age and birthweight. We accrued 157 person-years of observation (PYO) and detected 37 episodes of ILI (24/100 PYO) and 83 episodes of malaria infection (including all new episodes of parasitemia) (53/100 PYO). ILI was the most common cause of fever, but was not associated with adverse pregnancy outcomes. ILI incidence peaked during the hot dry season. These results indicate that ILI is a significant burden among Malawian pregnant women and it is somewhat seasonal. Studies with molecular diagnostics are needed to establish influenza-specific burden and the potential role of vaccination.

To reduce HIV incidence, prevention programs centered on the use of antiretrovirals require scaling-up HIV testing and counseling (HTC). Home-based HTC services (HBHTC) increase HTC coverage, but HBHTC has only been evaluated during one-off campaigns. Two years after an initial HBHTC campaign (“round 1”), we conducted another HBHTC campaign (“round 2”) in Likoma (Malawi). HBHTC participation increased during round 2 among women (from 74 to 83 %, P

Malawian women in all sectors of society are suffering from social implications of unwanted pregnancy and unsafe abortion. Unwanted pregnancies occur among women who have limited access to family planning and safe abortion. A legally restrictive setting for safe abortion services leads many women to unsafe abortion, which has consequences for them and their families. In-depth interviews were conducted with 485 Malawian stakeholders belonging to different political and social structures. Interviewees identified the impact of unwanted pregnancy and unsafe abortion to be the greatest on young women. Premarital and extramarital pregnancies were highly stigmatized; stigma directly related to abortion was also found. Community-level discussions need to focus on reduction of stigma.

Background Contact tracing (CT) has rarely been used to improve HIV case-finding in sub-Saharan Africa because of concerns regarding privacy protection and possibly high costs.

Human leukocyte antigen (HLA) allele frequencies vary between different human populations, with implications both for the evolutionary pressures shaping those populations as well as for the outcome of new infectious epidemics. We defined HLA class I types in a well-described cohort of persons on Likoma Island in Malawi, a population for which there are lacking data on allelic frequencies. The profile of HLA frequencies was similar but phylogenetically distinct from those of other sub-Saharan African populations in neighboring regions. The most common A alleles included A30, A23, A28 (A*68), and A2, and the most common B alleles included B15 (group), B53, B58, and B44. Notably, the frequency of B53, which is protective against malaria, was similar to that of other malaria-endemic African countries, and higher than that in countries with less malaria. This is the first reported significant dataset of HLA class I allelic frequencies in Malawians.

Concurrent partnerships (CPs) can accelerate the transmission of HIV (and other sexually transmitted infections) in a population [1–4]. CPs have been described as the “key driver” of generalized HIV epidemics [5]. Long-term CPs (i.e., partnerships that overlap for months, possibly years) in particular, may play a crucial role in connecting the sexual networks that transmit HIV [6]. Despite a recent surge of interest in targeting CPs for HIV prevention [7], the evidence that they are an important risk factor of HIV transmission remains limited [8–12]. The lack of association between partnership concurrency and HIV infection in empirical investigations could in part be due to the poor quality of survey data on CPs. To estimate the extent of CPs, survey respondents are typically asked questions about their 3–5 most recent sexual partners, including the dates at first and last sex, as well as whether the relationship with a given partner is still ongoing. These questions are used to check whether relationship intervals overlap [13, 14]. Such data are potentially affected by large biases [15–19], but few studies have evaluated the impact of measurement errors on survey estimates of partnership concurrency [14, 20], particularly in sub-Saharan settings. Only Morris and O'Gorman [15] argued that “measurement errors introduce a slight positive bias in estimates of the prevalence of CPs, and a slight negative bias in the length of the overlap [between CPs]”. This pioneering study suffers from two major limitations however: first, it only considered the impact of date heaping and recall errors on survey reports of partnership dates, but it did not consider the likely hypothesis that partnership histories (on which estimates are based) may not be reliable; second, it hypothesized that reporting errors occurred at random among population members, in ways that are unrelated to parameters of partnership concurrency. If patterns of misreporting are associated with partnership duration (for example), biases in concurrency measurements are likely to be significantly larger than previously thought. We use sociocentric network data collected on Likoma (an island located in the northern region of Lake Malawi) to (i) assess the inter-partner reliability of partnership histories collected during sexual behaviors surveys, and (ii) test whether reliability varies with partnership duration and timing. In doing so, and contrary to Morris and O'Gorman's previous assessment, we show that biases in survey measurements of CPs are large and of unknown direction.

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. Trial registration NCT00852423

Background: During pregnancy, women living in malaria-endemic regions are at increased risk of malaria infection and can harbour chronic placental infections. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPTp) is administered to reduce malaria morbidity. It was hypothesized that the presence of placental malaria infection and SP-IPTp use would increase the risk of peripheral blood gametocytes, the parasite stage that is transmissible to mosquitoes. This would suggest that pregnant women may be important reservoirs of malaria transmission. Methods: Light microscopy was used to assess peripheral gametocytaemia in pregnant women enrolled in a longitudinal, observational study in Blantyre, Malawi to determine the association between placental malaria and maternal gametocytaemia. The relationship between SP-IPTp and gametocytaemia was also examined. Results: 2,719 samples from 448 women were analysed and 32 episodes of microscopic gametocytaemia were detected in 27 women. At the time of enrolment 22 of 446 women (4.9%) had gametocytaemia and of the 341 women for whom there was sufficient sampling to analyse infection over the entire course of pregnancy, 27 (7.9%) were gametocytaemic at least once. Gametocytaemia at enrolment was associated with placental malaria, defined as malaria pigment or parasites detected by histology or qPCR, respectively (OR: 32.4, 95% CI: 4.2-250.2), but was not associated with adverse maternal or foetal outcomes. Administration of SP-IPTp did not affect gametocyte clearance or release into peripheral blood. Conclusions: Gametocytaemia is present in 5% of pregnant women at their first antenatal visit and associated with placental malaria. SP-IPTp does not alter the risk of gametocytaemia. These data suggest that pregnant women are a significant reservoir of gametocyte transmission and should not be overlooked in elimination efforts. Interventions targeting this population would benefit from reaching women prior to first antenatal visit.

Background Malaria during pregnancy results in adverse outcomes for mothers and infants. Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) is the primary intervention aimed at reducing malaria infection during pregnancy. Although submicroscopic infection is common during pregnancy and at delivery, its impact throughout pregnancy on the development of placental malaria and adverse pregnancy outcomes has not been clearly established. Methods Quantitative PCR was used to detect submicroscopic infections in pregnant women enrolled in an observational study in Blantyre, Malawi to determine their effect on maternal, foetal and placental outcomes. The ability of SP to treat and prevent submicroscopic infections was also assessed. Results 2,681 samples from 448 women were analysed and 95 submicroscopic infections were detected in 68 women, a rate of 0.6 episodes per person-year of follow-up. Submicroscopic infections were most often detected at enrolment. The majority of women with submicroscopic infections did not have a microscopically detectable infection detected during pregnancy. Submicroscopic infection was associated with placental malaria even after controlling for microscopically detectable infection and was associated with decreased maternal haemoglobin at the time of detection. However, submicroscopic infection was not associated with adverse maternal or foetal outcomes at delivery. One-third of women with evidence of placental malaria did not have documented peripheral infection during pregnancy. SP was moderately effective in treating submicroscopic infections, but did not prevent the development of new submicroscopic infections in the month after administration. Conclusions Submicroscopic malaria infection is common and occurs early in pregnancy. SP-IPT can clear some submicroscopic infections but does not prevent new infections after administration. To effectively control pregnancy-associated malaria, new interventions are required to target women prior to their first antenatal care visit and to effectively treat and prevent all malaria infections.

The Malawi Longitudinal Study of Families and Health (MLSFH) is one of very few longstanding, publicly available longitudinal cohort studies in a sub-Saharan African (SSA) context. It provides a rare record of more than a decade of demographic, socioeconomic and health conditions in one of the world’s poorest countries. The MLSFH was initially established in 1998 to study social network influences on fertility behaviours and HIV risk perceptions, and over time the focus of the study expanded to include health, sexual behaviours, intergenerational relations and family/household dynamics. The currently available data include MLSFH rounds collected in 1998, 2001, 2004, 2006, 2008, 2010 and 2012 for up to 4 000 individuals, providing information about socioeconomic and demographic characteristics, sexual behaviours, marriage, household/family structure, risk perceptions, social networks and social capital, intergenerational relations, HIV/AIDS and other dimensions of health. The MLSFH public use data can be requested on the project website: http://www.malawi.pop.upenn.edu/.

Background Malaria during pregnancy is associated with an increased risk for low birth weight (

The Likoma network study (LNS) investigates the sexual networks connecting the inhabitants of Likoma, a small island of Lake Malawi with high HIV prevalence. Whereas previous studies of sexual networks and HIV/AIDS in sub-Saharan countries have focused solely on the personal networks of a small number of respondents, the LNS attempts to document the sexual networks of the entire adult population of Likoma. To do so, it uses a unique sociocentric study design, in which all members of the local population are contacted for a survey interview and are asked to nominate their five most recent sexual partners. Using these data, quasi-complete ‘maps’ of the sexual networks connecting inhabitants of the island can be constructed. These maps allow investigation of the impact of networks on HIV epidemiology and can inform mathematical models of HIV prevention. In addition to data on sexual networks, the LNS data include information on the social networks (e.g. friendship), socioeconomic characteristics and HIV status of Likoma’s residents. Baseline data were collected in 2005–06. A first follow-up was conducted in 2007–08 and a second follow-up is planned for early 2013. Access to the LNS data is contingent upon review of a short concept paper and forming collaborations with LNS investigators.

Human immunodeficiency virus (HIV) is common in pregnant women in many malaria-endemic regions and may increase risk of placental parasitemia. Placental malaria is more common in primigravidae than multigravidae, but the relationship between HIV and malaria across gravidities is not well characterized. We recruited pregnant Malawian women during the second trimester and followed them until delivery. Parasitemia was assessed at enrollment, follow-up visits, and delivery, when placental blood was sampled. There was no difference in risk of parasitemia between HIV-positive and HIV-negative primigravidae. Among multigravidae, HIV-infected women had greater than twice the risk of parasitemia as HIV-uninfected women throughout follow-up. Human immunodeficiency virus was also associated with more frequent peripheral parasitemia in multigravidae but not primigravidae. Both HIV and primigravid status were independently associated with higher peripheral and placental parasite densities. Although risk of parasitemia is lower in multigravidae than primigravidae, the HIV effect on risk of malaria is more pronounced in multigravidae.

Background Malaria still remains a life-threatening disease worldwide causing between 190 and 311 million cases of malaria in 2008. Due to increased resistance to sulphadoxine-pyrimethamine (SP), the Ministry of Health in Malawi, as in many sub-Saharan African countries, changed the malaria treatment policy to use artemisinin-based combination therapy (ACT). In order to optimize the correct use of this drug, and protect against the development of the parasite's resistance, it is important to assess the knowledge and practices of medical practitioners on the use of ACT and its impact on adherence to new treatment policy guidelines. Methods A cross-sectional survey was conducted to assess the knowledge and perceptions of Malawian medical doctors and pharmacists on the use of ACT and the drivers of treatment choice and clinical treatment decisions. Medical doctors and pharmacists who are involved in managing malaria patients in Malawi were recruited and a self-administered questionnaire was used to obtain information on socio-demographic characteristics of the study participants, knowledge on ACT, source of information on ACT and methods used to decide on the treatment of patients with malaria. Results Most of the participants (95.7%) know at least one form of ACT, 67.4% reported that different forms of ACT have different characteristics, 77.3% reported that there are special formulations for children. The most commonly mentioned ACT was artemether-lumefantrine (AL), by 94.6% of the participants and 75.0% of the participants indicated that they prefer to prescribe AL. 73.9% of participants had ever received information on ACT. However, only 31.5% had received training on management of malaria using ACT. There were 71.7% respondents who had heard of ACT causing side effects. Only 25.0% of the participants had received training on how to report SAEs. Conclusion It was found that most of the participants know about ACT and treatment guidelines for malaria. However, most of the participants have not received any training on how to use ACT and how to report adverse effects arising from the use of ACT. There is need for more training of health care professionals to ensure correct and effective use of ACT.

Objective To assess the fertility and pregnancy experiences of rural Malawian women living with obstetric fistula and following surgical repair of fistula. Methods Fertility histories were collected via in-depth interviews with women identified in 2007 as having obstetric fistula and with their family members. Results Of the 32 affected women interviewed, 17 (53.1%) conceived after developing obstetric fistula: 13 before repair and 6 after repair (with 2 conceiving both pre- and post-repair). Complaints of infertility were more frequent and urgent among women who had undergone repair than among those who had not. Over half (53.8%) of the women who conceived while living with obstetric fistula and all of those who conceived post-repair experienced at least 1 spontaneous abortion or perinatal death. Nineteen (47.5%) of the 40 pregnancies among women living with obstetric fistula and 7 (70.0%) of the 10 pregnancies among women post-repair ended in spontaneous abortion or perinatal death. Conclusion Even 2 years after undergoing surgical repair, women can continue to experience the effects of obstetric fistula, which include infertility, spontaneous abortion, and perinatal mortality. The factors responsible for extensive infertility and poor pregnancy outcome in women post-repair warrant further investigation.

IntroductionThe objective of the study was to find out factors that affect the intentions of men and women to use family planning methods.MethodsThe study was conducted in Mangochi district, the southern regionof Malawi in 2006. About 60 Focus group discussions were conducted to identify the attitudes and beliefs of 30 male and 30 female participantsregarding family planning methods. The data was then transcribed and analyzed manually identifying central themes and relationships across the cases and narratives.ResultsMost of the respondents knew the different types of family planning methods and reported that health facilities had adequate stock of family planning supplies. However, it was found that most of the women and men were not using any modern family planning methods. Reasons included: family planning methods were perceived side effects, such as prolonged menstruation, men’s concerns about impotence and genital sores, weight gain or loss, and subsequent infertility. Traditional family planning methods were mostly used for infertility problems.ConclusionDespite knowing about the different types of family planning methods, and awareness of their ready availability in health facilities, use of these methods is low because considerable misinformation still prevails regarding contraceptive methods’ side effects.

To estimate the prevalence of obstetric fistula in Malawi and explore the potential risk factors for developing the condition.A community survey was conducted in 9 districts in Malawi, recruiting 3282 women aged at least 12 years using the sibling based method to identify cases of obstetric fistula. Hospital records from 9 district hospitals involved in the community survey and all hospitals offering fistula repair services in Malawi were reviewed.A total of 1107 women with obstetric fistula were identified: 575 from the community survey and 532 from hospital records. Median age was 29 years (range, 12-89 years). The prevalence of obstetric fistula was 1.6 per 1000 women. Women endured the condition for a median duration of 3 years. Comparison of women with and without obstetric fistula revealed significant differences in age (P=0.02), occupation (P0.01), and tribal origin (P=0.02), but no differences in education level (P=0.73) or religion (P=0.08).Obstetric fistula remains a major problem in Malawi. Increased awareness of the condition, improvement of maternal care services, and an increase in skilled personnel to perform fistula repair are needed to reduce the burden of this condition.