The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria

<p>Abstract</p> <p>Background</p> <p>Mefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children.</p> <p>Methods</p> <p>Children, aged between three months and five years, with acute uncomplicated <it>Plasmodium falciparum </it>malaria were randomized to either 7 days of artesunate monotherapy or the same schedule of artesunate plus mefloquine on day 7 and 8. Neurological testing targeting coordination and behaviour was carried out at day 0, 7, 9, 10, 14 and 28. Non-febrile healthy control children from the same population were tested on days 0, 7, 14 and 28.</p> <p>Results</p> <p>From December 1994 to July 1997, 91 children with uncomplicated <it>P. falciparum</it>, 45 treated with artesunate monotherapy, 46 treated with mefloquine and artesunate combination therapy and 36 non-febrile controls, underwent neurological testing. Malaria and fever had a significant negative impact on testing performance. By contrast, the anti-malarial treatments were not associated with worsening performances in the various components of the test. Artesunate and mefloquine do not appear to have a significant influence on coordination and behaviour. Children treated with mefloquine were significantly less likely to suffer recurrent malaria infection during follow-up compared to those treated with artesunate alone (P = 0.033).</p> <p>Conclusion</p> <p>In keeping with the results of randomized controlled trials in adults, mefloquine was not associated with a decrease in specific items of neurological performance. Likewise, children treated with artesunate did not perform significantly differently to control children. This study does not exclude subtle or rare treatment CNS effects of artesunate or mefloquine. Treatment of acute uncomplicated malaria results in a significant improvement on items of neurological performance.</p

Interactions between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium falciparum parasites and delivery outcomes in Malawi.

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 (www.isrctn.com/ISRCTN69800930) comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped PCR-detected parasites using deep sequencing of SP-resistance alleles. RESULTS Among 125 placental infections, A581G-bearing parasites were associated with reduced birthweight (mean difference[MD]:252g, 95% CI:46,457, p=0.017). Relative to ISTp, IPTp-SP was associated with higher birthweights in women with wildtype parasites (MD:116g, 95% CI:-40,272; p=0.142) and lower birthweights in women with A581G-bearing parasites (MD:192g, 95% CI:-264,648; p=0.385) (pinteraction=0.033). Similar associations were noted on gestational age (pinteraction=0.075). Amongst only IPTp-SP recipients, relative to women who last received SP >4 weeks before delivery, recent SP receipt was associated with lower birthweight in women with wildtype parasites (MD:118g, 95% CI:-376,139; p=0.361) and higher birthweight in women with A581G-bearing parasites (MD:783g, 95% CI:-20,1586; p=0.054) (pinteraction=0.005). CONCLUSIONS The effectiveness on birthweight 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

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

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

Impact of malaria diagnostic choice on monitoring of Plasmodium falciparum prevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance and Plasmodium falciparum prevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March–June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within Kinshasa Province, DRC. Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA. P. falciparum parasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4–72.4% across assays), followed by Kimpoko (32.6–53.2%), and Voix du Peuple (3.1–8.4%). Using latent class analysis to compare these diagnostic methods against an “alloyed gold standard,” the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimated P. falciparum prevalence by microscopy, PCR, and BBA were nearly double that of RDT. Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting any P. falciparum infection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions

Minimal impact by antenatal subpatent P. falciparum infections on delivery outcomes in Malawian women: a cohort study.

Antenatal malaria screening with a rapid diagnostic test (RDT) and treatment only of RDT-positive women may potentially prevent low birthweight 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 were tested at each antenatal visit for P. falciparum using RDT and PCR and followed until delivery. Associations between antenatal infections and delivery outcomes were assessed with Poisson regression or ANOVA. Compared to women with no detected antenatal P. falciparum infections, women with RDT-positive infections delivered babies with lower mean birthweights: 2960 vs 2867 grams[g] (mean difference[MD]: -93g; 95% confidence interval[CI]: -27,-159; p=0.006); this was not observed among women with only subpatent infections (mean: 3013g; MD: +54; 95% CI: -33,+140; p=0.2268). These differences were apparent early in pregnancy: At second trimester enrollment, compared to uninfected women, RDT-positive women delivered babies with lower mean birthweight (MD: -94g; 95% CI: -31,-156; p=0.003), but women with subpatent infections did not (MD: +36g; 95% CI: -49,+122; p=0.409). Subpatent antenatal P. falciparum infections were not associated with adverse delivery outcomes. The association of patent infections at enrollment with low birthweight suggests the importance of early-pregnancy P. falciparum prevention

Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial

Background In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP. Methods and Findings This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI −3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90–1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92–1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71–1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%–12.63%]; all women: RR = 1.19 [95% CI 1.07–1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04–1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02–1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01–4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design. Conclusions Scheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery

Flow chart.

<p>^aOne woman randomized to IPTp-SP was erroneously recorded as being in the ISTp-DP arm on her antenatal care card and as a result received ISTp-DP. She was included in the ITT population under the IPTp-SP arm. ^bScreening failures were not followed to delivery and were excluded from the modified ITT population. ^cWomen lost to follow-up prior to delivery and women who withdrew consent were included in the ITT population and contributed to the antenatal follow-up analyses (e.g., incidence of malaria). IPTp-SP, intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine; ISTp-DP, intermittent screening and treatment in pregnancy with dihydroartemisinin-piperaquine; ITT, intention to treat; SGA/LBW/PT, small for gestational age or low birthweight or preterm.</p

Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria.

PURPOSE: We compared the pharmacokinetics of chloroquine in pregnant and nonpregnant women treated for Plasmodium vivax malaria. METHODS: Twelve pregnant women and 15 nonpregnant women of child-bearing age with acute P. vivax malaria were treated with 25 mg chloroquine base/kg over 3 days on the northwestern border of Thailand. Blood concentrations of chloroquine and desethylchloroquine were measured using hydrophilic interaction liquid chromatography coupled with fluorescence detection. Twenty-five women completed the pharmacokinetic study. RESULTS: Although increasing gestational age was associated with reduced chloroquine AUC0-->infinity, there was no significant difference overall in the pharmacokinetics of chloroquine between pregnant and nonpregnant women. Fever was associated with lower chloroquine AUC0-->infinity values. Desethylchloroquine area under the curve (AUC) values were not significantly affected by pregnancy. CONCLUSIONS: Pregnancy did not significantly affect blood concentrations of chloroquine or its metabolite, desethylchloroquine, in women with P. vivax malaria