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Background: Pregnancy is both a risk factor for P. falciparum infection and development of severe malaria. In low- and middle-income countries, the COVID-19 pandemic severely impacted health systems, including utilization of maternal services. This study aimed to assess trends in delivering malaria in pregnancy-related health-care services before and during COVID-19 in Northern Uganda., Methods: An interrupted time-series study comparing pre-COVID-19 (January 2018 to April 2020) and COVID-19 (May to December 2021) periods, based on the date the first COVID case was detected. The study involved 30 health facilities in Northern Uganda with 22,650 estimated pregnancies per year, 14% of which took place in hospital. Monthly data were sourced from District routinely collected indicators. Trends were analyzed by joinpoint regression models., Results: From the onset of the COVID pandemic in Uganda (May 2020), we found a significant reduction in the number of women accessing a fourth antenatal care visit (from APC + 183.5 to + 4.98; p  < 0.001) and taking at least three doses of intermittent preventive treatment in pregnancy (IPTp, from APC + 84.28 to -63.12; p  < 0.001). However, we found no significant change in the trend of the total number of pregnant women managed as outpatients or hospitalized for malaria, as well as in the number of women attending their first antenatal visit and in the number of institutional deliveries., Conclusions: In our study, the COVID-19 pandemic significantly reduced access to ANC visits and IPTp uptake. However, the healthcare system maintained its capacity for managing malaria cases, first antenatal visits, and institutional deliveries.Trial registration: This study has been registered on the ClinicalTrials.gov public website on 26 April 2022. ClinicalTrials.gov Identifier: NCT05348746.

Background: Malaria in pregnancy contributes to substantial morbidity and mortality among women in Uganda. However, there is limited information on the prevalence and factors associated with malaria in pregnancy among women in Arua district, northwestern Uganda. We, therefore, assessed the prevalence and factors associated with malaria in pregnancy among women attending routine antenatal care (ANC) clinics at Arua regional referral hospital in north-western Uganda., Methods: We conducted an analytic cross-sectional study between October and December 2021. We used a paper-based structured questionnaire to collect data on maternal socio-demographic and obstetric factors and malaria preventive measures. Malaria in pregnancy was defined as a positive rapid malarial antigen test during ANC visits. We performed a modified Poisson regression analysis with robust standard errors to determine factors independently associated with malaria in pregnancy, reported as adjusted prevalence ratios (aPR) and 95% confidence intervals (CI)., Results: We studied 238 pregnant women with a mean age of 25.32±5.79 years that attended the ANC clinic, all without symptomatic malaria. Of the participants, 173 (72.7%) were in their second or third trimester, 117 (49.2%) were first or second-time pregnant women, and 212 (89.1%) reported sleeping under insecticide-treated bednets (ITNs) every day. The prevalence of malaria in pregnancy was 26.1% (62/238) by rapid diagnostic testing (RDT), with the independently associated factors being daily use of insecticide-treated bednets (aPR 0.41, 95% CI 0.28, 0.62), first ANC visit after 12 weeks of gestation (aPR1.78, 95% CI 1.05, 3.03), and being in the second or third trimester (aPR 0.45, 95% CI 0.26, 0.76)., Conclusion: The prevalence of malaria in pregnancy among women attending ANC in this setting is high. We recommend the provision of insecticide-treated bednets to all pregnant women and early ANC attendance to enable access to malaria preventive therapy and related interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mangusho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In spite of the missed opportunities of sulfadoxine-pyrimethamine (IPTp-SP) in Uganda, scanty literature exist on malaria in pregnancy. To date, empirical national study utilizing the 2018-19 Uganda Malaria Indicator Survey to explore predictors of attaining three or more doses of IPTp-SP in the country is non-existent. This study investigated the factors affecting uptake of three or more IPTp-SP doses as recommended by the World Health Organization., Methods: Data from the 2018-2019 Uganda Malaria Indicator Survey (2018-19 UMIS) was analysed. Adequate uptake of intermittent preventive therapy with IPTp-SP was the dependent variable for this study. Weighted frequencies and percentages were used to present the proportion of women who had adequate IPTp-SP uptake or otherwise with respect to the independent variables. A three-level multilevel logistic regression was fitted. The Bayesian Deviance Information Criterion (DIC) was used in determining the goodness of fit of all the models., Results: Less than half of the surveyed women had three or more IPTp-SP doses during their last pregnancies (45.3%). Women aged 15-19 had less odds of receiving at least three IPTp-SP doses compared to those aged 45-49 [aOR = 0.42, Crl = 0.33-0.98]. Poor women [aOR = 0.80, Crl = 0.78-0.91] were less likely to have three or more doses of IPTp-SP relative to rich women. Most disadvantaged regions were aligned with less likelihood of three or more IPTp-SP uptake [aOR = 0.59, CI = 0.48-0.78] compared to least disadvantaged regions. The variation in uptake of three or more IPTp-SP doses was substantial at the community level [σ 2  = 1. 86; Crl = 11.12-2.18] than regional level [σ 2  = 1.13; Crl = 1.06-1.20]. About 18% and 47% disparity in IPTp-SP uptake are linked to region and community level factors respectively., Conclusion: IPTp-SP interventions need to reflect broader community and region level factors in order to wane the high malaria prevalence in Uganda. Contextually responsive behavioural change communication interventions are required to invoke women's passion to achieve the recommended dosage., (© 2022. The Author(s).)

Background: Consistent use of insecticide-treated nets (ITNs) and intermittent preventive treatment in pregnancy (IPTp) have been recommended as cost-effective interventions for malaria prevention during pregnancy in endemic areas. However, the coverage and utilization of these interventions during pregnancy in sub-Saharan Africa is still suboptimal. This study aimed to determine the uptake of IPTp and ITNs and associated factors among women during their recent pregnancy in Eastern Uganda., Methods: This was a cross-sectional study conducted among 2062 women who had delivered within the last 12 months prior to the start of the study in three districts of Eastern Uganda. The primary outcomes were consistent ITN use and optimal uptake (at least 3 doses) of IPTp. A modified Poisson regression was used to examine the association between consistent ITN use and the uptake of optimal doses of IPTp with independent variables. Data were analysed using Stata 14 software., Results: The level of uptake of IPTp3 (at least three doses) was 14.7%, while IPTp2 (at least two doses) was 60.0%. The majority (86.4%) of mothers reported regularly sleeping under mosquito nets for the full duration of pregnancy. Uptake of IPTp3 was associated with engaging in farming (adjusted PR = 1.71, 95% CI [1.28-2.28]) or business (adjusted PR = 1.60, 95% CI [1.05-2.44]), and attending at least 4 antenatal care (ANC) visits (adjusted PR = 1.72, 95% CI [1.34-2.22]). On the other hand, consistent ITN use was associated with belonging to the fourth wealth quintile (adjusted PR = 1.08, 95% CI [1.02-1.14]) or fifth wealth quintile (adjusted PR = 1.08, 95% CI [1.02-1.15]), and attending at least 4 ANC visits (adjusted PR = 1.07, 95% CI [1.03-1.11])., Conclusion: Uptake of IPTp3 and consistent ITN use during pregnancy were lower and higher than the current Ugandan national targets, respectively. Study findings highlight the need for more efforts to enhance utilization of ANC services, which is likely to increase the uptake of these two key malaria preventive measures during pregnancy.

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Uganda ranks third in the number of deaths attributable to malaria and has some of the highest recorded malaria transmission rates in the general population. Malaria in Pregnancy is associated with detrimental effects for the mother and unborn baby and these effects seem to have long term effects and consequences on the life of the baby. Despite the preventive measures put in place by the World Health Organization in antenatal care, the burden of malaria in pregnancy is still high. We determined the use of malaria preventive strategies during pregnancy and the presence of plasmodium infection, anemia, and low birth weight babies at delivery among parturient women at Mbale regional referral hospital in eastern Uganda., Methods: A cross-sectional study was conducted among 210 women delivering at MRRH between July 2017 and January 2018. Information on demographics, antenatal care, and prevention practices was collected using an interviewer-administered questionnaire. Maternal venous blood and cord blood samples were screened for Plasmodium infection by both microscopy of Giemsa-stained blood films and Plasmodium falciparum rapid diagnostic test (pf. HPR2 mRDT). Polymerase Chain Reaction (PCR) was done on cord blood. The presence of anemia was determined by the use of an automated hemoglobin analyzer. Data were analyzed using descriptive and analytical statistics., Results: Of the 210 women, 3 (1.4%) and 19(9.1%) tested positive for malaria by using Giemsa stained blood smear microscopy and malaria rapid diagnosticMRDT tests respectively. PCR detected 4(%) of Plasmodium in cord blood. Twenty-nine percent of the women had anaemia and 11 (5.2%) had low birth weight babies. Only 23.3% of the women received at least three doses of IPTp-SP and 57.9% reported sleeping under an Insecticide Treated Net the night before the survey. The women who reported sleeping under a mosquito net the previous night (OR 0.67, 95% CI: 0.24-1.86) and those who reported taking fansidar as a directly observed therapy (OR 0.31, 95% CI: 0.04-2.39) appeared to have few chances of getting plasmodium infection though the findings were not statistically significant., Conclusion: The effective use of malaria preventive strategies (IPT-SP and Insecticide Treated Nets) was generally low. Most of the women took less than three doses of SP and there was no strict adherence to the recommended directly observed therapy. The prevalence of Plasmodium infection during pregnancy was low though maternal anaemia and low birth weight were relatively high., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Despite recent large-scale investments, malaria remains a major public health concern. Few studies have examined congenital malaria, defined as the presence of malaria parasitemia within the first 7 days of life, in endemic areas. This study aimed to determine the prevalence, to describe the clinical presentation, and to examine factors associated with congenital malaria in newborns aged up to 7 days attending Tororo General Hospital in Uganda. A total of 261 mother/baby pairs were recruited in this cross-sectional study. Giemsa-stained thick blood smears for malaria parasites and rapid malaria diagnostic tests were performed on capillary blood samples from all newborns and mothers, as well as on placental and cord samples from newborns delivered in the hospital. The prevalence of congenital malaria in the newborns was 16/261 (6.1%). No single clinical feature was associated with congenital malaria. However, there were associations between congenital malaria and maternal parasitemia ( P < 0.001), gravidity of one ( P = 0.03), maternal age < 19 years ( P = 0.01), cord blood parasitemia ( P = 0.01), and placental malaria ( P = 0.02). In conclusion, congenital malaria is not rare in Uganda and there are no obvious clinical features associated with it in the newborn. Based on these findings, we recommend strengthening malaria prevention during pregnancy to reduce the occurrence of congenital malaria in newborns.

Background: Intermittent treatment with sulfadoxine-pyrimethamine, recommended for prevention of malaria in pregnant women throughout sub-Saharan Africa, is threatened by parasite resistance. We assessed the efficacy and safety of intermittent preventive treatment with dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine., Methods: We did a double-blind, randomised, controlled, superiority trial at one rural site in Uganda with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-uninfected pregnant women between 12 and 20 weeks gestation were randomly assigned (1:1) to monthly intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine. The primary endpoint was the risk of a composite adverse birth outcome defined as low birthweight, preterm birth, or small for gestational age in livebirths. Protective efficacy was defined as 1-prevalence ratio or 1-incidence rate ratio. All analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02793622., Findings: Between Sept 6, 2016, and May 29, 2017, 782 women were enrolled and randomly assigned to receive sulfadoxine-pyrimethamine (n=391) or dihydroartemisinin-piperaquine (n=391); 666 (85·2%) women who delivered livebirths were included in the primary analysis. There was no significant difference in the risk of our composite adverse birth outcome between the dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine treatment group (54 [16%] of 337 women vs 60 [18%] of 329 women; protective efficacy 12% [95% CI -23 to 37], p=0·45). Both drug regimens were well tolerated, with no significant differences in adverse events between the groups, with the exception of asymptomatic corrected QT interval prolongation, which was significantly higher in the dihydroartemisinin-piperaquine group (mean change 13 ms [SD 23]) than in the sulfadoxine-pyrimethamine group (mean change 0 ms [SD 23]; p<0·0001)., Interpretation: Monthly intermittent preventive treatment with dihydroartemisinin-piperaquine was safe but did not lead to significant improvements in birth outcomes compared with sulfadoxine-pyrimethamine., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Bill & Melinda Gates Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa ( pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections ( pfmdr1 : N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt : K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier NCT02282293.)., (Copyright © 2019 American Society for Microbiology.)

Poor health worker performance is a well-documented obstacle to quality service provision. Due to the increasingly widespread availability of mobile devices, mobile health (mHealth) has received growing attention as a service improvement tool. This pilot study explored feasibility, acceptability and outcomes of an mHealth intervention designed to increase coverage of intermittent preventive treatment of malaria in pregnancy (IPTp) in two districts of West Nile, Uganda. In both districts, selected health workers (N = 48) received classroom training on malaria in pregnancy. All health workers in one district (N = 49) subsequently received 24 text messages reinforcing the training content. The intervention was evaluated using a mixed-methods approach, including four focus group discussions with health workers and three in-depth interviews with district health officials, health worker knowledge assessments one month (N = 90) and six months (N = 89) after the classroom training, and calculation of IPTp coverage from participating health facilities' (N = 16) antenatal care registers covering six months pre- and post-intervention. Complementing classroom training with text messaging was found to be a feasible, acceptable and inexpensive approach to improving health worker performance. The messages served as reminders to those who had attended the classroom training and helped spread information to those who had not. Health workers in the district where text messages were sent had significantly better knowledge of IPTp, achieving an increased composite knowledge score of 6.00 points (maximum score: 40) compared with those in the district where only classroom training was provided. Average facility coverage of three doses of IPTp was also significantly higher where text messages were sent (85.8%) compared with the district where only classroom training was provided (54.1%). This intervention shows promise for the improvement of health worker performance for delivery of IPTp, and could have significant broader application., Competing Interests: The authors have declared that no competing interests exist.

Background: Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP., Methods and Findings: We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy., Conclusions: Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy., Trial Registration: ClinicalTrials.gov number NCT02163447., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: (1) EC declared NIH research grants to institution; (2) DVH declared that they received grant funding from NIH. For studies outside of submitted work, they received antiretroviral therapy for NIH funded study from Gilead Sciences; (3) JB is a member of the Editorial Board of PLOS Medicine.

Background: Congenital malaria is the direct infection of an infant with malaria parasites from their mother prior to or during birth. Neonatal malaria is due to an infective mosquito bite after birth. Neonatal and congenital malaria (NCM) are potentially life-threatening conditions that are believed to occur at relatively low rates in malaria endemic regions. However, recent reports suggest that the number of NCM cases is increasing, and its epidemiology remains poorly described. NCM can mimic other neonatal conditions and because it is thought to be rare, blood film examinations for malaria are not always routinely performed. Consequently, many cases of NCM are likely to be undiagnosed. A retrospective chart review for all neonates admitted with suspected sepsis between January and July 2017 was conducted and noted four cases of NCM since routine malaria testing was introduced as part of standard of care for suspected sepsis at Mbale Regional Referral Hospital Neonatology Unit. This description highlights the need to conduct routine malaria diagnostic testing for febrile neonates in malaria endemic areas, and supports the urgent need to undertake pharmacological studies on therapeutic agents in this population., Case Presentation: Four cases (two congenital malaria cases and two neonatal malaria cases) are described after presenting for care at the Mbale Regional Referral Hospital Neonatal Unit (Mbale RRH-NNU). The maternal age was similar across the cases, but both neonatal malaria cases were born to primigravidae. At presentation three cases had fever and history of fever, but one was hypothermic (34.8 °C) and no history of fever. One case of congenital malaria had low birth weight, while the other was born to an HIV positive mother. Both cases of congenital malaria presented with poor feeding, in addition one of them had clinical jaundice. The neonatal malaria cases presented in the third week compared to the congenital malaria cases that presented within 48 h after birth. All of the cases of NCM were treated with intravenous artesunate. The admitting clinicians also instituted a course of antibiotics empirically to cover against possible bacterial co-infections. All four cases recovered and were discharged alive., Conclusion: At the Mbale RRH-NNU, the finding of cases of NCM was not expected, therefore, neonates presenting with features of suspected sepsis in malaria endemic settings should be routinely screened for NCM. There is currently a lack of appropriate guidelines for treatment of NCM in the era of artemisinin-based combination therapy (ACT), therefore, efforts to establish the safety profile and efficacy of ACT anti-malarials in neonates to guide development of evidence-based treatment guidelines for NCM are needed.

Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC 0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC 0-21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC 0-8hr and piperaquine AUC 0-21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed., Methods: We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria., Results: The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events., Conclusions: The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely implemented in sub-Saharan Africa for the prevention of malaria in pregnancy and adverse birth outcomes. However, in areas of intense SP resistance, the efficacy of IPTp may be compromised., Methods: A cross-sectional study among 915 delivering women (728 analysable live singleton deliveries) was conducted in Fort Portal, western Uganda, to assess associations of reported IPTp use, Plasmodium falciparum infection, maternal anaemia, low birth weight, and preterm delivery, and to estimate the degree of SP resistance as reflected by pfdhfr/pfdhps mutations., Results: Plasmodium falciparum infection was detected by PCR in 8.9 % and by microscopy of placental blood samples in 4.0 %. Infection was significantly associated with stillbirth, early neonatal death, anaemia, low birth weight, and pre-term delivery. Eighty percent of the women had taken at least one dose of IPTp, and more than half had taken two doses. As compared to women without chemoprophylaxis against malaria, IPTp had no significant influence on the presence of P. falciparum infection (13.8 vs. 9.6 %, P = 0.31). Nor was it associated with reductions in anaemia, low birth weight or preterm delivery. P. falciparum with intense SP resistance (pfdhfr/pfdhps quintuple or sextuple mutations) were observed in 93 % (pfdhps 581G, 36 %), and the additional high resistance allele pfhdr 164L in 36 %., Conclusions: In Fort Portal, Uganda, reported use of IPTp with SP does not provide an observable benefit. The molecular markers of P. falciparum indicate high grade SP resistance reaching the threshold set by WHO for the discontinuation of IPTp with SP. Alternative approaches for the prevention of malaria in pregnancy are urgently needed.

Background: The WHO recommends supervised administration of sulphadoxine-pyrimethamine (SP) as intermittent preventive treatment for malaria (IPTp) during pregnancy. Logistical constraints have however favoured unsupervised intake of SP-IPTp, casting doubts whether recent guidelines requiring more frequent intake can be effectively implemented. To propose strategies for enhancing compliance under limited supervision, this study sought to identify pregnant women's knowledge and practices gaps as well as determine predictors of compliance with SP-IPTp, given under limited supervision., Methods: A cross-sectional study of 700 women used exit interviews at an urban clinic in Uganda to obtain a descriptive summary of demographic and obstetric characteristics, including knowledge, practice and experiences with SP. Predictors of compliance with SP intake instructions were explored using logistic regression., Results: Median age of respondents was 25 (IQR 22-28) and median parity was two (IQR one to three) while median number of antenatal clinic (ANC) visits was 3.0 (IQR three to four). Most women had completed primary (36%) or ordinary secondary education (25.6%) while 16.1% had not completed primary education. Awareness about SP was high (99.4%) although correct knowledge regarding its use in pregnancy was low (57%), with 15.4% thinking it was used to treat malaria and 26.7% lacking any idea about its use. Correct knowledge on SP use during pregnancy significantly predicted compliance with SP-IPTp instructions (OR 1.98, C.I. 1.12-3.55), while age, education level, parity, number of ANC visits, or history of unwanted effects with SP did not. SP was mostly accessed from hospitals (64.4%) followed by private clinics (16.9%) both for preventive and treatment purposes. SP was considered safe by most women, who were willing to take it again in future, without supervision., Conclusion: Despite high awareness, knowledge of SP as an intervention for malaria prevention in pregnancy was low. Correct knowledge on use of SP predicted compliance with SP-IPTp intake instructions. Focused malaria-related education during ANC visits may improve compliance with SP intake amidst limited supervision.

Background: Maternal malaria is associated with serious adverse pregnancy outcomes. One recommended means of preventing malaria during pregnancy is intermittent preventive therapy (IPTp) with sulfadoxine/pyrimethamine (SP). We sought to identify determinants of preventive use of SP during pregnancy among recently pregnant women in Uganda. Additionally, we characterized the timing of and indications for the administration of SP at antenatal care (ANC) visits and missed opportunities for SP administration., Methodology/principal Findings: Utilizing a population-based random sample, we interviewed 500 women living in Jinja, Uganda who had been pregnant in the past year. Thirty-eight percent (192/500) of women received SP for the treatment of malaria and were excluded from the analysis of IPTp-SP. Of the remaining women, 275 (89.3%) reported at least two ANC visits after the first trimester and had an opportunity to receive IPTp-SP according to the Ugandan guidelines, but only 86 (31.3%) of these women received a full two-dose course of IPTp. The remaining 189 (68.7%) women missed one or more doses of IPTp-SP. Among the 168 women that were offered IPTp, 164 (97.6%) of them took the dose of SP., Conclusions/significance: Use of IPTp in Uganda was found to be far below target levels. Our results suggest that women will take SP for IPTp if it is offered during an ANC visit. Missed opportunities to administer IPTp-SP during ANC were common in our study, suggesting provider-level improvements are needed.

Access and compliance to sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) when delivered by community-directed drug distributors (CDDs) of ivermectin for onchocerciasis control (intervention arm) and through delivery of SP-IPTp during antenatal care visit (control arm) was investigated in western Uganda. Every woman in both arms who delivered during the study period was interviewed on access and compliance to SP-IPT during her previous pregnancy. Overall, 926 women participated in the study (473 and 453 in the intervention and control arms, respectively). There were 467 (98.7%) women who accessed SP-IPTp at least once in the intervention arm and 401 (88.5%) in the control arm (P<0.001), and 424 (89.6%) women accessed at least two doses of SP-IPTp in the intervention arm compared with 237 (52.3%) in the control arm (P<0.001). The findings of this study suggest that a strategy using community resource people such as CDDs is an effective and feasible option to deliver SP-IPTp, because it uses existing community structures and volunteers, which creates easy access of the intervention, and should complement SP-IPTp access during antenatal care visit.

The main objective of this study was to assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilisers could administer intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women. The study was implemented in 21 community clusters (intervention) and four clusters where health centres provided routine IPTp (control). The primary outcome measures were the proportion of women who completed two doses of SP; the effect on anaemia, parasitaemia and low birth weight; and the incremental cost-effectiveness of the intervention. The study enrolled 2785 pregnant women. The majority, 1404/2081 (67.5%) receiving community-based care, received SP early and adhered to the two recommended doses compared with 281/704 (39.9%) at health centres (P<0.001). In addition, women receiving community-based care had fewer episodes of anaemia or severe anaemia and fewer low birth weight babies. The cost per woman receiving the full course of IPTp was, however, higher when delivered via community care at US$2.60 compared with US$2.30 at health centres, due to the additional training costs. The incremental cost-effectiveness ratio of the community delivery system was Uganda shillings 1869 (US$1.10) per lost disability-adjusted life-year (DALY) averted. In conclusion, community-based delivery increased access and adherence to IPTp and was cost-effective.

Background: To reduce the intolerable burden of malaria in pregnancy, the Ministry of Health in Uganda improved the antenatal care package by including a strong commitment to increase distribution of insecticide-treated nets (ITNs) and introduction of intermittent preventive treatment with sulphadoxine-pyrimethamine for pregnant women (IPTp-SP) as a national policy in 2000. This study assessed uptake of both ITNs and IPTp-SP by pregnant women as well as antenatal and maternity care use with the aim of optimizing their delivery., Methods: 769 post-partum women were recruited from a rural area of central Uganda with perennial malaria transmission through a cross-sectional, community-based household survey in May 2005., Results: Of the 769 women interviewed, antenatal clinic (ANC) attendance was high (94.4%); 417 (57.7%) visiting initially during the 2nd trimester, 242 (33.5%) during the 3rd trimester and 266 (37.1%) reporting > or = 4 ANC visits. About 537 (71%) and 272 (35.8%) received one or > or = 2 IPTp-SP doses respectively. Only 85 (15.8%) received the first dose of IPTp-SP in the 3rd trimester. ITNs were used by 239 (31.3%) of women during pregnancy and 314 (40.8%) delivered their most recent pregnancy outside a health facility. Post-partum women who lacked post-primary education were more likely not to have attended four or more ANC visits (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.2-9.3)., Conclusion: These findings illustrate the need to strengthen capacity of the district to further improve antenatal care and maternity services utilization and IPTp-SP uptake. More specific and effective community health strategies to improve effective ANC, maternity services utilization and IPTp-SP uptake in rural communities should be undertaken.

Objective: The main objective of the study was to assess the impact of a community-based delivery system of intermittent preventive treatment (IPT) for malaria in pregnancy with sulfadoxine-pyrimethamine (SP) on access, parasitemia, anemia and low birth weight as primary outcome measures., Methods: A study was designed to test the community-based delivery system of IPT through traditional birth attendants (TBAs), drug-shop vendors (DSVs), community reproductive health workers (CRHWs) and adolescent peer mobilizers (APMs), and to compare these with IPT at health units in an area of high malaria transmission - Mukono District, Uganda., Results: Two thousand seven hundred and eighty-five pregnant women participated in the study. The majority of the women (92.4%) at the community-based approaches received their first dose of IPT during their second trimester compared to 76.1% at health units (p<0.0001). At both health units and the community-based approaches, IPT increased mean hemoglobin by 6.7% (p<0.0001) for all parities and by 10.2% among primigravidae. IPT reduced the prevalence of severe anemia from 5.7% to 3.1% (p<0.04). The prevalence of parasitemia was reduced from 24.5% to 16.1% (p<0.001), and parasite density reduced significantly (p<0.02) after the first dose and remained stable with the second dose. Overall the proportion of low birth weight was 6.3% (8.3% at health units versus 6.0% at the community-based approaches, p<0.03) highlighting the importance of access and adherence to IPT. This intervention was acceptable to 89.6% of the women at the community-based approaches intending to use IPT in the future, while 48.1% of them had recommended it to other women., Conclusions: The community-based approaches increased access and adherence to IPT with an effect on anemia, severe anemia, parasitemia and low birth weight. However the reduced effect of IPT on parasitemia points to drug resistance with SP and this requires further evaluation; research into the identification of other more efficacious drugs for malaria prevention in pregnancy is also required.

The effects of weekly chloroquine prophylaxis, daily iron-weekly folic acid supplementation or passive case management on maternal haemoglobin and parasitaemia and on birthweight were examined in primigravidae in a randomized, double-blind placebo-controlled intervention trial in 1996-98 in Hoima District, western Uganda. Iron-folic acid supplementation significantly increased mean birthweight as compared to case management (P = 0.03). Low birthweight (< 2.5 kg) occurred in 2% of babies of women receiving chloroquine prophylaxis for > or = 8 weeks and in 9% in the case management group (RR = 0.36, 95% CI 0.13-1.00, P = 0.009). Parasitaemia at enrolment significantly correlated with low birthweight in the case management group as compared to the intervention groups (P = 0.02). Women in the case management group who were parasitaemia and had haemoglobin levels < 100 g/L at delivery had babies with lower mean birthweight as compared to babies in the other groups (P = 0.04). Low haemoglobin level at enrolment, irrespective of parasitaemia status, was a predictor of low birthweight in the case management group only (P = 0.04). Chloroquine prophylaxis and iron-folic acid supplementation significantly increased maternal haemoglobin levels during pregnancy as compared to case management (P = 0.01 and 0.007, respectively) and the increase correlated to the duration of the intervention.