Publications by authors named "Julie Gutman"

76 Publications

Piperaquine Pharmacokinetics during Intermittent Preventive Treatment for Malaria in Pregnancy.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption ( = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.).
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http://dx.doi.org/10.1128/AAC.01150-20DOI Listing
February 2021

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

Malar J 2020 Nov 30;19(1):438. Epub 2020 Nov 30.

National Institute for Medical Research, Dar Es Salaam, United Republic of Tanzania.

Background: In areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy.

Methods: Data from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%.

Results: Over the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise been missed. Among the 15.9% of women detected in the first trimester, 50.7% were asymptomatic.

Conclusion: In areas of moderate/high transmission, many infected women were asymptomatic, and would have been missed in the absence of SST. The benefits on maternal and fetal birth outcomes of identifying these infections depend heavily on the protection afforded by treatment, which is likely to be greatest for women presenting in the first trimester when intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) is contraindicated, and in areas with high SP resistance, such as most parts of Tanzania. An evaluation of the impact and cost-effectiveness of SST across different transmission strata is warranted.
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http://dx.doi.org/10.1186/s12936-020-03513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708125PMC
November 2020

Cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine for malaria during pregnancy: an analysis using efficacy results from Uganda and Kenya, and pooled data.

Lancet Glob Health 2020 12 30;8(12):e1512-e1523. Epub 2020 Oct 30.

Faculty of Public Health and Policy, Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, UK.

Background: Prevention of malaria infection during pregnancy in HIV-negative women currently relies on the use of long-lasting insecticidal nets together with intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). Increasing sulfadoxine-pyrimethamine resistance in Africa threatens current prevention of malaria during pregnancy. Thus, a replacement for IPTp-SP is urgently needed, especially for locations with high sulfadoxine-pyrimethamine resistance. Dihydroartemisinin-piperaquine is a promising candidate. We aimed to estimate the cost-effectiveness of intermittent preventive treatment in pregnancy with dihydroartemisinin-piperaquine (IPTp-DP) versus IPTp-SP to prevent clinical malaria infection (and its sequelae) during pregnancy.

Methods: We did a cost-effectiveness analysis using meta-analysis and individual trial results from three clinical trials done in Kenya and Uganda. We calculated disability-adjusted life-years (DALYs) arising from stillbirths, neonatal death, low birthweight, mild and moderate maternal anaemia, and clinical malaria infection, associated with malaria during pregnancy. Cost estimates were obtained from data collected in observational studies, health-facility costings, and from international drug procurement databases. The cost-effectiveness analyses were done from a health-care provider perspective using a decision tree model with a lifetime horizon. Deterministic and probabilistic sensitivity analyses using appropriate parameter ranges and distributions were also done. Results are presented as the incremental cost per DALY averted and the likelihood that an intervention is cost-effective for different cost-effectiveness thresholds.

Findings: Compared with three doses of sulfadoxine-pyrimethamine, three doses of dihydroartemisinin-piperaquine, delivered to a hypothetical cohort of 1000 pregnant women, averted 892 DALYs (95% credibility interval 274 to 1517) at an incremental cost of US$7051 (2653 to 13 038) generating an incremental cost-effectiveness ratio (ICER) of $8 (2 to 29) per DALY averted. Compared with monthly doses of sulfadoxine-pyrimethamine, monthly doses of dihydroartemisinin-piperaquine averted 534 DALYS (-141 to 1233) at a cost of $13 427 (4994 to 22 895), resulting in an ICER of $25 (-151 to 224) per DALY averted. Both results were highly robust to most or all variations in the deterministic sensitivity analysis.

Interpretation: Our findings suggest that among HIV-negative pregnant women with high uptake of long-lasting insecticidal nets, IPTp-DP is cost-effective in areas with high malaria transmission and high sulfadoxine-pyrimethamine resistance. These data provide a comprehensive overview of the current evidence on the cost-effectiveness of IPTp-DP. Nevertheless, before a policy change is advocated, we recommend further research into the effectiveness and costs of different regimens of IPTp-DP in settings with different underlying sulfadoxine-pyrimethamine resistance.

Funding: Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Hygiene and Tropical Medicine.
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http://dx.doi.org/10.1016/S2214-109X(20)30369-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686013PMC
December 2020

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

Malar J 2020 Aug 5;19(1):282. Epub 2020 Aug 5.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, US Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop H24-3, Atlanta, GA, 30329, USA.

Background: Malaria in pregnancy is responsible for 8-14% of low birth weight and 20% of stillbirths in sub-Saharan Africa. To prevent these adverse consequences, the World Health Organization recommends intermittent preventive treatment of pregnant women (IPTp) with sulfadoxine-pyrimethamine be administered at each ANC visit starting as early as possible in the second trimester. Global IPTp coverage in targeted countries remains unacceptably low. Community delivery of IPTp was explored as a means to improve coverage.

Methods: A cluster randomized, controlled trial was conducted in 12 health facilities in a 1:1 ratio to either an intervention group (IPTp delivered by CHWs) or a control group (standard practice, with IPTp delivered at HFs) in three districts of Burkina Faso to assess the effect of IPTp administration by community health workers (CHWs) on the coverage of IPTp and antenatal care (ANC). The districts and facilities were purposively selected taking into account malaria epidemiology, IPTp coverage, and the presence of active CHWs. Pre- and post-intervention surveys were carried out in March 2017 and July-August 2018, respectively. A difference in differences (DiD) analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level.

Results: Altogether 374 and 360 women were included in the baseline and endline surveys, respectively. At baseline, women received a median of 2.1 doses; by endline, women received a median of 1.8 doses in the control group and 2.8 doses in the intervention group (p-value < 0.0001). There was a non-statistically significant increase in the proportion of women attending four ANC visits in the intervention compared to control group (DiD = 12.6%, p-value = 0.16). By the endline, administration of IPTp was higher in the intervention than control, with a DiD of 17.6% for IPTp3 (95% confidence interval (CI) - 16.3, 51.5; p-value 0.31) and 20.0% for IPTp4 (95% CI - 7.2, 47.3; p-value = 0.15).

Conclusions: Community delivery of IPTp could potentially lead to a greater number of IPTp doses delivered, with no apparent decrease in ANC coverage.
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http://dx.doi.org/10.1186/s12936-020-03356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409482PMC
August 2020

Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa.

Nat Commun 2020 07 30;11(1):3799. Epub 2020 Jul 30.

Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.

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.
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http://dx.doi.org/10.1038/s41467-020-17528-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393377PMC
July 2020

Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis.

Lancet Glob Health 2020 07;8(7):e942-e953

Department of Disease Control, Faculty of Infectious and Tropical Disease, London School of Hygiene & Tropical Medicine, London, UK.

Background: Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine.

Methods: We defined treatment as random assignment to sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine before pooling individual participant-level data from 1617 HIV-uninfected pregnant women in Kenya (one trial; n=806) and Uganda (two trials; n=811). We quantified the relative effect of treatment on birthweight (primary outcome) attributed to preventing placental malaria infection (mediator). We estimated antimalarial (indirect) and non-malarial (direct) effects of IPTp on birth outcomes using causal mediation analyses, accounting for confounders. We used two-stage individual participant data meta-analyses to calculate pooled-effect sizes.

Findings: Overall, birthweight was higher among neonates of women randomly assigned to sulfadoxine-pyrimethamine compared with women assigned to dihydroartemisinin-piperaquine (mean difference 69 g, 95% CI 26 to 112), despite placental malaria infection being lower in the dihydroartemisinin-piperaquine group (relative risk [RR] 0·64, 95% CI 0·39 to 1·04). Mediation analyses showed sulfadoxine-pyrimethamine conferred a greater non-malarial effect than did dihydroartemisinin-piperaquine (mean difference 87 g, 95% CI 43 to 131), whereas dihydroartemisinin-piperaquine conferred a slightly larger antimalarial effect than did sulfadoxine-pyrimethamine (8 g, -9 to 26), although more frequent dosing increased the antimalarial effect (31 g, 3 to 60).

Interpretation: IPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight.

Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation, and Worldwide Antimalarial Resistance Network.
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http://dx.doi.org/10.1016/S2214-109X(20)30119-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303957PMC
July 2020

Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy.

Lancet Infect Dis 2020 08 29;20(8):880-881. Epub 2020 Apr 29.

Department of Disease Control, Faculty of Infectious and Tropical Disease, London School of Hygiene & Tropical Medicine, London, UK.

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http://dx.doi.org/10.1016/S1473-3099(20)30131-6DOI Listing
August 2020

Malaria and Parasitic Neglected Tropical Diseases: Potential Syndemics with COVID-19?

Am J Trop Med Hyg 2020 08 1;103(2):572-577. Epub 2020 Jun 1.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.

The COVID-19 pandemic, caused by SARS-CoV-2, have surpassed 5 million cases globally. Current models suggest that low- and middle-income countries (LMICs) will have a similar incidence but substantially lower mortality rate than high-income countries. However, malaria and neglected tropical diseases (NTDs) are prevalent in LMICs, and coinfections are likely. Both malaria and parasitic NTDs can alter immunologic responses to other infectious agents. Malaria can induce a cytokine storm and pro-coagulant state similar to that seen in severe COVID-19. Consequently, coinfections with malaria parasites and SARS-CoV-2 could result in substantially worse outcomes than mono-infections with either pathogen, and could shift the age pattern of severe COVID-19 to younger age-groups. Enhancing surveillance platforms could provide signals that indicate whether malaria, NTDs, and COVID-19 are syndemics (synergistic epidemics). Based on the prevalence of malaria and NTDs in specific localities, efforts to characterize COVID-19 in LMICs could be expanded by adding testing for malaria and NTDs. Such additional testing would allow the determination of the rates of coinfection and comparison of severity of outcomes by infection status, greatly improving the understanding of the epidemiology of COVID-19 in LMICs and potentially helping to mitigate its impact.
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http://dx.doi.org/10.4269/ajtmh.20-0516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410484PMC
August 2020

Malaria in the pregnant traveler.

J Travel Med 2020 Jul;27(4)

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.

Pregnant travelers face numerous risks, notably increased susceptibility to or severity of multiple infections, including malaria. Because pregnant women residing in areas non-endemic for malaria are unlikely to have protective immunity, travel to endemic areas poses risk of severe illness and pregnancy complications, such as low birthweight and fetal loss. If travel to malaria-endemic areas cannot be avoided, preventive measures are critical. However, malaria chemoprophylaxis in pregnancy can be challenging, since commonly used regimens have varying levels of safety data and national guidelines differ. Furthermore, although chloroquine and mefloquine have wide acceptance for use in pregnancy, regional malaria resistance and non-pregnancy contraindications limit their use. Mosquito repellents, including N,N-diethyl-m-toluamide (DEET) and permethrin treatment of clothing, are considered safe in pregnancy and important to prevent malaria as well as other arthropod-borne infections such as Zika virus infection. Pregnant travelers at risk for malaria exposure should be advised to seek medical attention immediately if any symptoms of illness, particularly fever, develop.
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http://dx.doi.org/10.1093/jtm/taaa074DOI Listing
July 2020

The impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC.

Nat Commun 2020 04 30;11(1):2107. Epub 2020 Apr 30.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA.

The Democratic Republic of the Congo (DRC) harbors 11% of global malaria cases, yet little is known about the spatial and genetic structure of the parasite population in that country. We sequence 2537 Plasmodium falciparum infections, including a nationally representative population sample from DRC and samples from surrounding countries, using molecular inversion probes - a high-throughput genotyping tool. We identify an east-west divide in haplotypes known to confer resistance to chloroquine and sulfadoxine-pyrimethamine. Furthermore, we identify highly related parasites over large geographic distances, indicative of gene flow and migration. Our results are consistent with a background of isolation by distance combined with the effects of selection for antimalarial drug resistance. This study provides a high-resolution view of parasite genetic structure across a large country in Africa and provides a baseline to study how implementation programs may impact parasite populations.
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http://dx.doi.org/10.1038/s41467-020-15779-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192906PMC
April 2020

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

Malar J 2020 Apr 15;19(1):154. Epub 2020 Apr 15.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), 1600 Clifton Rd. NE, Mailstop A06, Atlanta, GA, 30322, USA.

Background: The World Health Organization recommends three or more doses of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) to mitigate the negative effects of malaria in pregnancy (MIP). Many pregnant women in Malawi are not receiving the recommended number of doses. Community delivery of IPTp (cIPTp) is being piloted as a new approach to increase coverage. This survey assessed recently pregnant women's knowledge of MIP and their experiences with community health workers (CHWs) prior to implementing cIPTp.

Methods: Data were collected via a household survey in Ntcheu and Nkhata Bay Districts, Malawi, from women aged 16-49 years who had a pregnancy resulting in a live birth in the previous 12 months. Survey questions were primarily open response and utilized review of the woman's health passport whenever possible. Analyses accounted for selection weighting and clustering at the health facility level and explored heterogeneity between districts.

Results: A total of 370 women were interviewed. Women in both districts found their community health workers (CHWs) to be helpful (77.9%), but only 35.7% spoke with a CHW about antenatal care and 25.8% received assistance for malaria during their most recent pregnancy. A greater proportion of women in Nkhata Bay than Ntcheu reported receiving assistance with malaria from a CHW (42.7% vs 21.9%, p = 0.01); women in Nkhata Bay were more likely to cite IPTp-SP as a way to prevent MIP (41.0% vs 24.8%, p = 0.02) and were more likely to cite mosquito bites as the only way to spread malaria (70.6% vs 62.0% p = 0.03). Women in Nkhata Bay were more likely to receive 3 + doses of IPTp-SP (IPTp3) (59.2% vs 41.8%, p = 0.0002). Adequate knowledge was associated with increased odds of receiving IPTp3, although not statistically significantly so (adjusted odds ratio = 1.50, 95% confidence interval 0.97-2.32, p-value 0.066).

Conclusions: Women reported positive experiences with CHWs, but there was not a focus on MIP. Women in Nkhata Bay were more likely to be assisted by a CHW, had better knowledge, and were more likely to receive IPTp3+ . Increasing CHW focus on the dangers of MIP and implementing cIPTp has the potential to increase IPTp coverage.
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http://dx.doi.org/10.1186/s12936-020-03228-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161231PMC
April 2020

Response to Behrens and Edwards: Atovaquone-proguanil exposure in pregnancy should not be condemned from current evidence.

Travel Med Infect Dis 2020 Mar - Apr;34:101599. Epub 2020 Feb 18.

Centers for Disease Control and Prevention, USA.

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http://dx.doi.org/10.1016/j.tmaid.2020.101599DOI Listing
February 2021

Proactive case detection of common childhood illnesses by community health workers: a systematic review.

BMJ Glob Health 2019 15;4(6):e001799. Epub 2019 Dec 15.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Identifying design features and implementation strategies to optimise community health worker (CHW) programmes is important in the context of mixed results at scale. We systematically reviewed evidence of the effects of proactive case detection by CHWs in low-income and middle-income countries (LMICs) on mortality, morbidity and access to care for common childhood illnesses.

Methods: Published studies were identified via electronic databases from 1978 to 2017. We included randomised and non-randomised controlled trials, controlled before-after studies and interrupted time series studies, and assessed their quality for risk of bias. We reported measures of effect as study investigators reported them, and synthesised by outcomes of mortality, disease prevalence, hospitalisation and access to treatment. We calculated risk ratios (RRs) as a principal summary measure, with CIs adjusted for cluster design effect.

Results: We identified 14 studies of 11 interventions from nine LMICs that met inclusion criteria. They showed considerable diversity in intervention design and implementation, comparison, outcomes and study quality, which precluded meta-analysis. Proactive case detection may reduce infant mortality (RR: 0.52-0.94) and increase access to effective treatment (RR: 1.59-4.64) compared with conventional community-based healthcare delivery (low certainty evidence). It is uncertain whether proactive case detection reduces mortality among children under 5 years (RR: 0.04-0.80), prevalence of infectious diseases (RR: 0.06-1.02), hospitalisation (RR: 0.38-1.26) or increases access to prompt treatment (RR: 1.00-2.39) because the certainty of this evidence is very low.

Conclusion: Proactive case detection may provide promising benefits for child health, but evidence is insufficient to draw conclusions. More research is needed on proactive case detection with rigorous study designs that use standardised outcomes and measurement methods, and report more detail on complex intervention design and implementation.

Prospero Registration Number: CRD42017074621.
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http://dx.doi.org/10.1136/bmjgh-2019-001799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936477PMC
December 2019

Determinants of uptake of intermittent preventive treatment during pregnancy: a review.

Malar J 2019 Nov 21;18(1):372. Epub 2019 Nov 21.

Malaria Branch, Division of Parasitic Diseases and Malaria, U.S Centers for Disease Control and Prevention, Atlanta, GA, USA.

Malaria in pregnancy (MiP) contributes to devastating maternal and neonatal outcomes. Coverage of intermittent preventive treatment during pregnancy (IPTp) remains alarmingly low. Data was compiled from MiP programme reviews and performed a literature search on access to and determinants of IPTp. National malaria control and reproductive health (RH) policies may be discordant. Integration may improve coverage. Medication stock-outs are a persistent problem. Quality improvement programmes are often not standardized. Capacity building varies across countries. Community engagement efforts primarily focus on promotion of services. The majority of challenges can be addressed at country level to improve IPTp coverage.
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http://dx.doi.org/10.1186/s12936-019-3004-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873519PMC
November 2019

Atovaquone-proguanil exposure in pregnancy and risk for adverse fetal and infant outcomes: A retrospective analysis.

Travel Med Infect Dis 2019 Nov 17:101519. Epub 2019 Nov 17.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Malaria in pregnancy can cause severe maternal and fetal complications. Chloroquine (CQ) and mefloquine (MQ) are recommended for chemoprophylaxis in pregnancy, but are not always suitable. Atovaquone-proguanil (AP) might be a viable option for malaria prevention in pregnancy, but more safety data are needed.

Methods: Data for pregnancies and live births among active duty military women, 2003-2014, from the Department of Defense Birth and Infant Health Research program were linked with pharmacy data to determine antimalarial exposure. Multivariable Cox and logistic regression models were used to assess the relationship of antimalarial exposure with fetal and infant outcomes, respectively.

Results: Among 198,164 pregnancies, 50 were exposed to AP, 156 to MQ, and 131 to CQ. Overall, 17.6% of unexposed pregnancies and 28.0%, 16.0%, and 6.1% of pregnancies exposed to AP, MQ, and CQ, respectively, ended in fetal loss (spontaneous abortion or stillbirth) (adjusted hazard ratios [aHR] = 1.46, 95% confidence interval [CI] 0.87-2.46; aHR = 1.06, 95% CI 0.72-1.57, and aHR = 0.47, 95% CI 0.24-0.94, respectively).

Conclusions: The small number of AP exposed pregnancies highlights the difficulty in assessing safety. While definitive conclusions are not possible, these data suggest further research of AP exposure in pregnancy and fetal loss is warranted.

Twitter Line: More research on fetal loss following atovaquone-proguanil exposure in pregnancy is warranted.
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http://dx.doi.org/10.1016/j.tmaid.2019.101519DOI Listing
November 2019

Estimating malaria burden among pregnant women using data from antenatal care centres in Tanzania: a population-based study.

Lancet Glob Health 2019 12;7(12):e1695-e1705

National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.

Background: More timely estimates of malaria prevalence are needed to inform optimal control strategies and measure progress. Since 2014, Tanzania has implemented nationwide malaria screening for all pregnant women within the antenatal care system. We aimed to compare malaria test results during antenatal care to two population-based prevalence surveys in Tanzanian children aged 6-59 months to examine their potential in measuring malaria trends and progress towards elimination.

Methods: Malaria test results from pregnant women screened at their first antenatal care visits at health-care facilities (private and public) in all 184 districts of Tanzania between Jan 1, 2014, and Dec 31, 2017, were collected from the Health Management Information Systems and District Health Information System 2. We excluded facilities with no recorded antenatal care attendees during the time period. We standardised results to account for testing uptake and weighted them by the timing of two population-based surveys of childhood malaria prevalence done in 2015-16 (Demographic and Health Survey) and 2017 (Malaria Indicator Survey). We assessed regional-level correlation using Spearman's coefficient and assessed the consistency of monthly district-level prevalence ranking using Kendall's correlation coefficient.

Findings: Correlation between malaria prevalence at antenatal care and among children younger than 5 years was high (r≥0·83 for both surveys), although declines in prevalence at antenatal care were generally smaller than among children. Consistent heterogeneity (p<0·05) in antenatal care prevalence at the district level was evident in all but one region (Kilimanjaro). Data from antenatal care showed declining prevalence in three regions (Arusha, Kilimanjaro, and Manyara) where surveys estimated zero prevalence.

Interpretation: Routine antenatal care-based screening can be used to assess heterogeneity in transmission at finer resolution than population-based surveys, and provides sample sizes powered to detect changes, notably in areas of low transmission where surveys lack power. Declines in prevalence at antenatal care might lag behind those among children, highlighting the value of monitoring burden and continuing prevention efforts among pregnant women as transmission declines. The pregnancy-specific benefits and cost-effectiveness of antenatal care-based screening remain to be assessed.

Funding: None.
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http://dx.doi.org/10.1016/S2214-109X(19)30405-XDOI Listing
December 2019

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

Clin Infect Dis 2020 Aug;71(4):1063-1071

Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya.

Background: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited.

Methods: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay.

Results: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001).

Conclusions: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic.

Clinical Trials Registration: NCT02687373.
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http://dx.doi.org/10.1093/cid/ciz925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428396PMC
August 2020

Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis.

Lancet Infect Dis 2019 05 25;19(5):546-556. Epub 2019 Mar 25.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK. Electronic address:

Background: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes.

Methods: For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540.

Findings: Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (p=0·0060) but not Ala437Gly (p=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and southern Africa]; n=30; p=0·0054 [univariate], I=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% [7 to 12]), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% [range 29 to 46]; RRR 0·5% [-16 to 14]; 2326 births).

Interpretation: The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%.

Funding: US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.
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http://dx.doi.org/10.1016/S1473-3099(18)30732-1DOI Listing
May 2019

Comparison of msp genotyping and a 24 SNP molecular assay for differentiating Plasmodium falciparum recrudescence from reinfection.

Malar J 2019 Mar 18;18(1):84. Epub 2019 Mar 18.

Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.

Background: Current World Health Organization guidelines for conducting anti-malarial drug efficacy clinical trials recommend genotyping Plasmodium falciparum genes msp1 and msp2 to distinguish recrudescence from reinfection. A more recently developed potential alternative to this method is a molecular genotyping assay based on a panel of 24 single nucleotide polymorphism (SNP) markers.

Methods: Performance parameters of these two genotyping methods were compared using data from two recently completed drug efficacy trials. Blood samples from two anti-malarial therapeutic trials were analysed by both msp genotyping and the 24 SNP assay. Additionally, to conserve time and resources, the statistical program R was used to select the most informative SNPs for a set of unrelated Malawian samples to develop a truncated SNP-based assay for the region surrounding Blantyre, Malawi. The ability of this truncated assay to distinguish reinfection from recrudescence when compared to the full 24 SNP assay was then analysed using data from the therapeutic trials.

Results: A total of 360 samples were analysed; 66 for concordance of msp and SNP barcoding methodologies, and 294 for assessing the most informative of the 24 SNP markers. SNP genotyping performed comparably to msp genotyping, with only one case of disagreement among the 50 interpretable results, where the SNP assay identified the sample as reinfection and the msp typing as recrudescence. Furthermore, SNP typing was more robust; only 6% of samples were uninterpretable by SNP typing, compared to 19.7% when msp genotyping was used. For discriminating reinfection from recrudescence, a truncated 6 SNP assay was found to perform at 95.1% the accuracy of the full 24 SNP bar code.

Conclusions: The use of SNP analysis has similar sensitivity to the standard msp genotyping in determining recrudescence from reinfection. Although more expensive, SNP typing is faster and less work intensive. Limiting the assay to those SNPs most informative in the geographical region of interest may further decrease the workload and the cost, making this technique a feasible and affordable alternative in drug efficacy trials.
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http://dx.doi.org/10.1186/s12936-019-2695-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423793PMC
March 2019

The safety of atovaquone-proguanil for the prevention and treatment of malaria in pregnancy: A systematic review.

Travel Med Infect Dis 2019 Jan - Feb;27:20-26. Epub 2019 Jan 14.

Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop A06, Atlanta, GA, 30329-4027, USA. Electronic address:

Background: Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence of adverse outcomes after atovaquone-proguanil (AP) exposure during pregnancy.

Methods: Following PRISMA guidelines, the authors searched PubMed, MEDLINE, and the Malaria in Pregnancy Consortium Library to identify relevant literature including infant outcomes after exposure to atovaquone, proguanil, or AP in pregnancy. Two authors independently screened the titles, abstracts, and full texts, and extracted data into an EpiInfo database. Overall proportions and 95% confidence intervals of adverse outcomes were determined by pooling data across studies.

Results: Of 455 records identified, 16 studies were included: ten AP studies and six proguanil studies. The overall proportions and 95% confidence intervals (CI) of adverse outcomes reported for the 446 women exposed to AP include miscarriage (8.08% CI: 5.07, 12.08%), stillbirth (1.05% CI: 0.03, 5.73%), early neonatal death (0% CI: 0, 7.4%), and congenital anomalies (2.56% CI: 1.28, 4.53%).

Conclusions: The limited available data suggest that outcomes following AP exposure during pregnancy are similar to expected rates in similar populations. AP may be a promising option for pregnant women, but further data are needed on its safety in pregnancy.
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http://dx.doi.org/10.1016/j.tmaid.2019.01.008DOI Listing
April 2019

Safety of atovaquone-proguanil during pregnancy.

J Travel Med 2019 Jun;26(4)

Malaria Branch, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Malaria during pregnancy increases the risk of maternal and foetal complications. There are very limited options for prophylaxis in pregnant travellers. Atovaquone-Proguanil (AP or Malarone®) is an effective and well-tolerated antimalarial medication, but is not recommended for use in pregnancy due to limited data on safety. Passively reported adverse event data may provide additional information on the safety of AP during pregnancy.

Methods: We analysed adverse event data on pregnancy and birth outcomes following accidental exposures to AP during pregnancy, which were passively reported to GlaxoSmithKline LLC (GSK) between 13 May 1997 and 15 August 2017. Birth outcomes of interest included live birth, miscarriage, and stillbirth. Adverse outcomes of interest were defined as any of the following: small for gestational age (SGA), low birth weight (LBW, <2500 gm), congenital anomalies, and a composite 'poor live birth outcome,' including preterm birth (PTB), LBW or SGA.

Results: Among 198 women who received AP during pregnancy or breastfeeding, 96.5% occurred in women taking malaria prophylaxis, and 79.8% of exposures occurred in the first trimester. Among 195 with available birth outcome data, 18.5% resulted in miscarriage and 11.8% were elective terminations. Available adverse outcomes included SGA in 3.5% (3/85), LBW in 7.0% of infants (6/86), and the composite 'poor live birth outcome' in 13.7% (14/102). Congenital anomalies were reported in 30/124 (24.2%), with no specific pattern to suggest an effect related to AP.

Conclusions: These data provide a description of outcomes in the pregnancies reported to this dataset, and it should be noted that there is likely a bias towards reporting cases resulting in poor outcomes. While there was no specific signal to suggest a teratogenic effect of AP, AP data during pregnancy were too limited to determine AP's safety with confidence. As inadvertent exposures are not infrequent, better data are needed.
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http://dx.doi.org/10.1093/jtm/tay138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590067PMC
June 2019

An analysis of country adoption and implementation of the 2012 WHO recommendations for intermittent preventive treatment for pregnant women in sub-Saharan Africa.

Malar J 2018 Oct 16;17(1):364. Epub 2018 Oct 16.

Malaria Branch, Center for Global Health, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop A06, Atlanta, GA, 30322, USA.

Background: An estimated 30 million women give birth annually in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy is associated with an increased risk of adverse maternal and infant outcomes. To combat the adverse effects of MiP, the World Health Organization (WHO) recommends the provision of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) in areas of moderate to high malaria transmission. In 2012, the WHO updated its policy with respect to IPTp administration to recommend administration at each antenatal care visit in the second and third trimesters, with a minimum of three, rather than two, doses. While rapid improvements in coverage were expected, gains have occurred more slowly than anticipated.

Methods: The President's Malaria Initiative (PMI) assessed IPTp uptake before and after countries implemented the new WHO policy, and assessed how long it took for implementation to occur, using a combination of data from household surveys, routine health management information systems, and programmatic data provided to PMI.

Results: It took an average of 2 years for countries to complete the process of revising their IPTp policies, and it was not until 2015 that all 17 PMI countries had updated their policies. Policy dissemination and training had not been completed in several countries as of early 2018, and only seven countries had fully implemented the new policy including updating their antenatal care registers to collect information on IPTp3+ coverage. The coverage of IPTp1+, 2+, and 3+ has increased by 19, 16, and 13 percentage points since the revised IPTp policy adoption.

Discussion: Overall, coverage of both IPTp2+ and IPTp3+ has improved in recent years. The change in policy from a minimum of two to a minimum of three doses has likely contributed to these improvements. Progress has been slow, likely related to the complicated process of policy adoption exacerbated by the lag in measurement through national household surveys. The impact of future policy changes may be more readily seen if the policy change and implementation process were more streamlined and coordinated between key stakeholders (National Malaria Control Programmes and Reproductive Health Programmes), with more real-time data reporting.
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http://dx.doi.org/10.1186/s12936-018-2512-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192297PMC
October 2018

A renewed focus on preventing malaria in pregnancy.

Reprod Health 2018 Jul 27;15(1):131. Epub 2018 Jul 27.

Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, USA.

While much progress has been achieved globally in the fight against malaria, the significant financial investments made to date have not translated into scaled-up malaria in pregnancy (MiP) prevention efforts. Mothers and newborns remain at risk, and now is the time to refocus efforts. Against the backdrop of a new global health architecture embodied by the principles of Every Women, Every Child and driven by the work of the H6 Partnership, Global Financing Facility, strong bilaterals and key financiers, there is a new and timely juncture to advocate for MiP. Recent updates in the WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience present an opportunity to strengthen MiP as a core maternal and child health issue and position MiP prevention as a priority.
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http://dx.doi.org/10.1186/s12978-018-0573-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062858PMC
July 2018

Malaria Diagnostic Practices in U.S. Laboratories in 2017.

J Clin Microbiol 2018 08 26;56(8). Epub 2018 Jul 26.

Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA.

In the United States, the gold standard for malaria diagnosis is microscopic blood smear examination. Because malaria is not endemic in the United States, diagnostic capabilities may be limited, causing delays in diagnosis and increased morbidity and mortality. A survey of the malaria diagnostic practices of U.S. laboratories was conducted from June to July 2017; members of the American Society for Microbiology's listserv received a questionnaire inquiring about malaria diagnostic test availability, techniques, and reporting. Results were assessed using the Clinical and Laboratory Standards Institute (CLSI) guidelines for malaria diagnostics. After excluding incomplete and duplicate responses, responses representing 175 laboratories were included. Most labs (99%) received at least one specimen annually for malaria diagnosis, and 31% reported receiving only 1 to 10 specimens. The majority (74%) diagnosed five or fewer cases of malaria per year. Most (90%) performed blood smears on-site. Two-thirds (70%) provided initial blood smear results within 4 h. Although diagnostic testing for malaria was available 24/7 at 74% (141) of responding laboratories, only 12% (17) met criteria for analysis and reporting of malaria testing, significantly more than reported in a similar survey in 2010 (3%; < 0.05). The majority of laboratories surveyed had the capability for timely diagnosis of malaria; few comply with CLSI guidelines. Inexperience may factor into this noncompliance; many laboratories see few to no cases of malaria per year. Although reported adherence to CLSI guidelines was higher than in 2010, there is a need to further improve laboratory compliance with recommendations.
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http://dx.doi.org/10.1128/JCM.00461-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062816PMC
August 2018

A survey on outcomes of accidental atovaquone-proguanil exposure in pregnancy.

Malar J 2018 May 15;17(1):198. Epub 2018 May 15.

Malaria Branch, Center for Global Health, Centers for Disease Control and Prevention, 1600 Clifton Rd. MS A6, Atlanta, GA, 30329, USA.

Background: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies.

Results: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects.

Conclusions: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.
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http://dx.doi.org/10.1186/s12936-018-2352-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952583PMC
May 2018

Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in the Democratic Republic of the Congo: A cluster-randomized, community-based non-inferiority trial.

PLoS Med 2018 04 17;15(4):e1002552. Epub 2018 Apr 17.

International Rescue Committee, New York, New York, United States of America.

Background: The World Health Organization's integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children.

Methods And Findings: We conducted a cluster-randomized, community-based non-inferiority trial among children 2-59 months old presenting to community health workers (CHWs) with non-severe unclassified fever in Tanganyika Province, Democratic Republic of the Congo. Clusters (n = 28) of CHWs were randomized to advise caregivers to either (1) return for a follow-up visit on day 3 following the initial consultation on day 1, regardless of illness resolution (as per current WHO guidelines; universal follow-up group) or (2) return for a follow-up visit on day 3 only if illness continued (conditional follow-up group). Children in both arms were assessed again at day 8, and classified as a clinical failure if fever (caregiver-reported), malaria, diarrhea, pneumonia, or decline of health status (development of danger signs, hospitalization, or death) was noted (failure definition 1). Alternative failure definitions were examined, whereby caregiver-reported fever was first restricted to caregiver-reported fever of at least 3 days (failure definition 2) and then replaced with fever measured via axillary temperature (failure definition 3). Study participants, providers, and investigators were not masked. Among 4,434 enrolled children, 4,141 (93.4%) met the per-protocol definition of receipt of the arm-specific advice from the CHW and a timely day 8 assessment (universal follow-up group: 2,210; conditional follow-up group: 1,931). Failure was similar (difference: -0.7%) in the conditional follow-up group (n = 188, 9.7%) compared to the universal follow-up group (n = 230, 10.4%); however, the upper bound of a 1-sided 95% confidence interval around this difference (-∞, 5.1%) exceeded the prespecified non-inferiority margin of 4.0% (non-inferiority p = 0.089). When caregiver-reported fever was restricted to fevers lasting ≥3 days, failure in the conditional follow-up group (n = 159, 8.2%) was similar to that in the universal follow-up group (n = 200, 9.1%) (difference: -0.8%; 95% CI: -∞, 4.1%; p = 0.053). If caregiver-reported fever was replaced by axillary temperature measurement in the definition of failure, failure in the conditional follow-up group (n = 113, 5.9%) was non-inferior to that in the universal follow-up group (n = 160, 7.2%) (difference: -1.4%; 95% CI: -∞, 2.5%; p = 0.012). In post hoc analysis, when the definition of failure was limited to malaria, diarrhea, pneumonia, development of danger signs, hospitalization, or death, failure in the conditional follow-up group (n = 108, 5.6%) was similar to that in the universal follow-up group (n = 147, 6.7%), and within the non-inferiority margin (95% CI: -∞, 2.9%; p = 0.017). Limitations include initial underestimation of the proportion of clinical failures as well as substantial variance in cluster-specific failure rates, reducing the precision of our estimates. In addition, heightened security concerns slowed recruitment in the final months of the study.

Conclusions: We found that advising caregivers to return only if children worsened or remained ill on day 3 resulted in similar rates of caregiver-reported fever and other clinical outcomes on day 8, compared to advising all caregivers to return on day 3. Policy-makers could consider revising guidelines for management of uncomplicated fever within the iCCM framework.

Trial Registration: ClinicalTrials.gov NCT02595827.
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http://dx.doi.org/10.1371/journal.pmed.1002552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903590PMC
April 2018

Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in Ethiopia: A cluster-randomised non-inferiority trial.

PLoS Med 2018 04 17;15(4):e1002553. Epub 2018 Apr 17.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, US Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

Background: With declining malaria prevalence and improved use of malaria diagnostic tests, an increasing proportion of children seen by community health workers (CHWs) have unclassified fever. Current community management guidelines by WHO advise that children seen with non-severe unclassified fever (on day 1) should return to CHWs on day 3 for reassessment. We compared the safety of conditional follow-up reassessment only in cases where symptoms do not resolve with universal follow-up on day 3.

Methods And Findings: We undertook a 2-arm cluster-randomised controlled non-inferiority trial among children aged 2-59 months presenting with fever and without malaria, pneumonia, diarrhoea, or danger signs to 284 CHWs affiliated with 25 health centres (clusters) in Southern Nations, Nationalities, and Peoples' Region, Ethiopia. The primary outcome was treatment failure (persistent fever, development of danger signs, hospital admission, death, malaria, pneumonia, or diarrhoea) at 1 week (day 8) of follow-up. Non-inferiority was defined as a 4% or smaller difference in the proportion of treatment failures with conditional follow-up compared to universal follow-up. Secondary outcomes included the percentage of children brought for reassessment, antimicrobial prescription, and severe adverse events (hospitalisations and deaths) after 4 weeks (day 29). From December 1, 2015, to November 30, 2016, we enrolled 4,595 children, of whom 3,946 (1,953 universal follow-up arm; 1,993 conditional follow-up arm) adhered to the CHW's follow-up advice and also completed a day 8 study visit within ±1 days. Overall, 2.7% had treatment failure on day 8: 0.8% (16/1,993) in the conditional follow-up arm and 4.6% (90/1,953) in the universal follow-up arm (risk difference of treatment failure -3.81%, 95% CI -∞, 0.65%), meeting the prespecified criterion for non-inferiority. There were no deaths recorded by day 29. In the universal follow-up arm, 94.6% of caregivers reported returning for reassessment on day 3, in contrast to 7.5% in the conditional follow-up arm (risk ratio 22.0, 95% CI 17.9, 27.2, p < 0.001). Few children sought care from another provider after their initial visit to the CHW: 3.0% (59/1,993) in the conditional follow-up arm and 1.1% (22/1,953) in the universal follow-up arm, on average 3.2 and 3.4 days later, respectively, with no significant difference between arms (risk difference 1.79%, 95% CI -1.23%, 4.82%, p = 0.244). The mean travel time to another provider was 2.2 hours (95% CI 0.01, 5.3) in the conditional follow-up arm and 2.6 hours (95% CI 0.02, 4.5) in the universal follow-up arm (p = 0.82); the mean cost for seeking care after visiting the CHW was 26.5 birr (95% CI 7.8, 45.2) and 22.8 birr (95% CI 15.6, 30.0), respectively (p = 0.69). Though this study was an important step to evaluate the safety of conditional follow-up, the high adherence seen may have resulted from knowledge of the 1-week follow-up visit and may therefore not transfer to routine practice; hence, in an implementation setting it is crucial that CHWs are well trained in counselling skills to advise caregivers on when to come back for follow-up.

Conclusions: Conditional follow-up of children with non-severe unclassified fever in a low malaria endemic setting in Ethiopia was non-inferior to universal follow-up through day 8. Allowing CHWs to advise caregivers to bring children back only in case of continued symptoms might be a more efficient use of resources in similar settings.

Trial Registration: www.clinicaltrials.gov, identifier NCT02926625.
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http://dx.doi.org/10.1371/journal.pmed.1002553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903591PMC
April 2018

Universal Versus Conditional Third Day Follow-Up Visit for Children With Nonsevere Unclassified Fever at the Community Level in Ethiopia: Protocol for a Cluster Randomized Noninferiority Trial.

JMIR Res Protoc 2018 Apr 12;7(4):e99. Epub 2018 Apr 12.

Malaria Branch, US Centers for Disease Control and Prevention, Atlanta, GA, United States.

Background: Under the World Health Organization's integrated community case management strategy, febrile children seen by community health workers (on day 1) without a diagnosable illness and without danger signs are advised to return on day 3, regardless of symptom resolution. This advice might be unnecessary and place additional time and cost burdens on caregivers and community health workers. However, the safety of not following up with respect to children with unclassified fever is unknown.

Objective: The objective of this study is to establish the safety of conditional follow-up of nonsevere unclassified fever, that is, nonsevere illness with fever, no malaria, pneumonia, diarrhea, or danger signs, compared with universal follow-up on day 3, through a 2-arm cluster randomized controlled noninferiority trial.

Methods: The study is being conducted in 3 districts in southwest Ethiopia. A total of 25 health facilities are randomized to one of the 2 intervention arms; all 144 health posts and 284 community health workers are included. All enrolled children are followed-up after 1 week (on day 8) for re-assessment. If still sick on day 8, additional follow-up takes place after 2 weeks (day 15) and 1 month (day 29). To demonstrate that there is no significant increase in the percentage of children deteriorating clinically, the sample size needed for a noninferiority margin of 4%, a power of 80%, an alpha of 5%, and a design effect of 3 is 4284 children with unclassified fever. Main outcome is treatment failure on day 8, defined as death, hospitalization, one or more danger signs, or persistent fever.

Results: The project was funded in 2015 and enrollment was completed 2016. Data analysis is currently under way, and the first results are expected to be submitted for publication in 2018.

Conclusions: This study addresses the question as to whether there is any benefit in recommending universal follow-up among children seen for nonsevere unclassified fever, or whether parents can be counseled to return in the event of persistent fever, using a cluster randomized controlled trial design embedded in a national program. Outcomes will be relevant for policy makers and are important for the evaluation of current and future World Health Organization guidelines for the management of children with fever.

Trial Registration: ClinicalTrials.gov NCT02926625; https://clinicaltrials.gov/ct2/show/NCT02926625 (Archived by WebCite at http://www.webcitation.org/6xrQWn50t).
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http://dx.doi.org/10.2196/resprot.9780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920148PMC
April 2018

Knowledge and Adherence to the National Guidelines for Malaria Diagnosis in Pregnancy among Health-Care Providers and Drug-Outlet Dispensers in Rural Western Kenya.

Am J Trop Med Hyg 2018 05 1;98(5):1367-1373. Epub 2018 Mar 1.

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, US Centers for Disease Control and Prevention, Atlanta, Georgia and Kenya.

Prompt diagnosis and effective treatment of acute malaria in pregnancy (MiP) is important for the mother and fetus; data on health-care provider adherence to diagnostic guidelines in pregnancy are limited. From September to November 2013, a cross-sectional survey was conducted in 51 health facilities and 39 drug outlets in Western Kenya. Provider knowledge of national diagnostic guidelines for uncomplicated MiP were assessed using standardized questionnaires. The use of parasitologic testing was assessed in health facilities via exit interviews with febrile women of childbearing age and in drug outlets via simulated-client scenarios, posing as pregnant women or their spouses. Overall, 93% of providers tested for malaria or accurately described signs and symptoms consistent with clinical malaria. Malaria was parasitologically confirmed in 77% of all patients presenting with febrile illness at health facilities and 5% of simulated clients at drug outlets. Parasitological testing was available in 80% of health facilities; 92% of patients evaluated at these facilities were tested. Only 23% of drug outlets had malaria rapid diagnostic tests (RDTs); at these outlets, RDTs were offered in 17% of client simulations. No differences were observed in testing rates by pregnancy trimester. The study highlights gaps among health providers in diagnostic knowledge and practice related to MiP, and the lack of malaria diagnostic capacity, particularly in drug outlets. The most important factor associated with malaria testing of pregnant women was the availability of diagnostics at the point of service. Interventions that increase the availability of malaria diagnostic services might improve malaria case management in pregnant women.
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http://dx.doi.org/10.4269/ajtmh.17-0594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953364PMC
May 2018

Treatment of uncomplicated and severe malaria during pregnancy.

Lancet Infect Dis 2018 04 31;18(4):e133-e146. Epub 2018 Jan 31.

Manhiça Health Research Center (CISM), Manhiça, Mozambique; Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique.

Over the past 10 years, the available evidence on the treatment of malaria during pregnancy has increased substantially. Owing to their relative ease of use, good sensitivity and specificity, histidine rich protein 2 based rapid diagnostic tests are appropriate for symptomatic pregnant women; however, such tests are less appropriate for systematic screening because they will not detect an important proportion of infections among asymptomatic women. The effect of pregnancy on the pharmacokinetics of antimalarial drugs varies greatly between studies and class of antimalarial drugs, emphasising the need for prospective studies in pregnant and non-pregnant women. For the treatment of malaria during the first trimester, international guidelines are being reviewed by WHO. For the second and third trimester of pregnancy, results from several trials have confirmed that artemisinin-based combination treatments are safe and efficacious, although tolerability and efficacy might vary by treatment. It is now essential to translate such evidence into policies and clinical practice that benefit pregnant women in countries where malaria is endemic. Access to parasitological diagnosis or appropriate antimalarial treatment remains low in many countries and regions. Therefore, there is a pressing need for research to identify quality improvement interventions targeting pregnant women and health providers. In addition, efficient and practical systems for pharmacovigilance are needed to further expand knowledge on the safety of antimalarial drugs, particularly in the first trimester of pregnancy.
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http://dx.doi.org/10.1016/S1473-3099(18)30065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590069PMC
April 2018