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Highly effective vector control can reduce malaria burden significantly, but individuals with parasitemia provide a potential reservoir for onward transmission. We performed an empirical, non-parametric simulation based on cohort data from Tororo District, Uganda-an area with historically high but recently reduced malaria transmission-to estimate the effects of mass drug administration (MDA) and test-and-treat on parasite prevalence. We estimate that a single round of MDA would have accelerated declines in parasite prevalence dramatically over 2 years (cumulative parasite prevalence ratio [PPR], 0.34). This decline was mostly during the first year of administration (PPR, 0.23) and waned by 23 months (PPR, 0.74). Test-and-treat using a highly sensitive diagnostic had nearly the same effect as MDA at 1 year (PPR, 0.27) and required many fewer treatments. The impact of test-and-treat using a standard diagnostic was modest (PPR, 0.58 at 1 year). Our analysis suggests that in areas experiencing a dramatic reduction in malaria prevalence, MDA or test-and-treat with a highly sensitive diagnostic may be an effective way of reducing or eliminating the infectious reservoir temporarily. However, for sustained benefits, repeated rounds of the intervention or additional interventions are required.

ObjectiveOur study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda.Study designForty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda.ResultsThe model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth

BackgroundIntermittent preventive treatment (IPT) of malaria with dihydroartemisinin-piperaquine is a promising strategy for malaria prevention in young African children. However, the optimal dosing strategy is unclear and conflicting evidence exists regarding the risk of malaria after cessation of chemoprevention. We aimed to compare two dosing strategies of IPT with dihydroartemisinin-piperaquine in young Ugandan children, and to evaluate the risk of malaria after cessation of IPT.MethodsIn this double-blind, randomised controlled phase 2 trial, women and their unborn children were recruited at Tororo District Hospital (Tororo, Uganda). Eligible participants were HIV-negative women aged 16 years or older with a viable pregnancy (gestational age 12-20 weeks). Women and their unborn children were randomly assigned (1:1:1:1) to one of four treatment groups, all receiving dihydroartemisinin-piperaquine, on the basis of the IPT intervention received by the woman during pregnancy: women every 8 weeks, children every 4 weeks; women every 4 weeks, children every 4 weeks; women every 8 weeks, children every 12 weeks; and women every 4 weeks, children every 12 weeks. Block randomisation was done by an independent investigator using a computer-generated randomisation list (permuted block sizes of six and 12). We analysed children on the basis of their random assignment to receive dihydroartemisinin-piperaquine (20 mg/160 mg tablets) once daily for 3 consecutive days every 4 weeks or 12 weeks. Children received study drugs from age 8 weeks to 24 months and were followed-up to age 36 months. Participants and investigators were masked to treatment allocation. The primary outcome was the incidence of symptomatic malaria during the intervention and following cessation of the intervention, adjusted for potential confounders. The primary outcome and safety were assessed in the modified intention-to-treat population, which included all children who reached 8 weeks of age and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02163447.FindingsBetween Oct 21, 2014, and May 18, 2015, 191 children were born, of whom 183 reached 8 weeks of age and received at least one dose of study drug and thus were included in the primary analysis (96 children in the 4-week group and 87 in the 12-week group). During the intervention, the incidence of symptomatic malaria was significantly lower among children treated every 4 weeks than children treated every 12 weeks; three episodes occurred among children treated every 4 weeks (incidence 0·018 episodes per person-year) compared with 61 episodes among children treated every 12 weeks (incidence 0·39 episodes per person-year; adjusted incidence rate ratio [aIRR] 0·041, 95% CI 0·012-0·150, p

Women living with HIV (WLHIV) have an increased risk of malaria in pregnancy (MiP). It is unclear if MiP in WLHIV causes a systemic inflammatory response and increases the risk of adverse birth outcomes, especially for women receiving antiretroviral therapy (ART) and daily trimethoprim-sulfamethoxazole (TMP/SXT). We analyzed repeated plasma samples in a cohort of malaria-exposed Ugandan WLHIV receiving ART and daily TMP/SXT to examine changes in inflammatory markers across pregnancy and their association with birth outcomes. Concentrations of CHI3L1, CRP, IL-18BP, IL-6, sICAM-1, and sTNFR2 were quantified by ELISA in 1115 plasma samples collected over pregnancy from 326 women. MiP was associated with increased sTNFR2, sICAM-1 and IL-18BP concentrations across pregnancy. Women who delivered preterm had elevated concentrations of sTNFR2 and altered levels of IL-6 during pregnancy. Women with sTNFR2 concentrations in the highest quartile within 6 weeks of delivery had an increased relative risk of preterm birth. Our results indicate that despite daily TMP/SXT, MiP in WLHIV induced a systemic inflammatory response that was associated with an increased risk of preterm birth. These findings highlight the need for additional strategies to protect WLHIV from malaria infection in pregnancy to promote healthy outcomes for mother and child.

Women living with HIV (WLHIV) have an increased risk of malaria in pregnancy (MiP). It is unclear if MiP in WLHIV causes a systemic inflammatory response and increases the risk of adverse birth outcomes, especially for women receiving antiretroviral therapy (ART) and daily trimethoprim-sulfamethoxazole (TMP/SXT). We analyzed repeated plasma samples in a cohort of malaria-exposed Ugandan WLHIV receiving ART and daily TMP/SXT to examine changes in inflammatory markers across pregnancy and their association with birth outcomes. Concentrations of CHI3L1, CRP, IL-18BP, IL-6, sICAM-1, and sTNFR2 were quantified by ELISA in 1115 plasma samples collected over pregnancy from 326 women. MiP was associated with increased sTNFR2, sICAM-1 and IL-18BP concentrations across pregnancy. Women who delivered preterm had elevated concentrations of sTNFR2 and altered levels of IL-6 during pregnancy. Women with sTNFR2 concentrations in the highest quartile within 6 weeks of delivery had an increased relative risk of preterm birth. Our results indicate that despite daily TMP/SXT, MiP in WLHIV induced a systemic inflammatory response that was associated with an increased risk of preterm birth. These findings highlight the need for additional strategies to protect WLHIV from malaria infection in pregnancy to promote healthy outcomes for mother and child.

BackgroundIntermittent 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 findingsWe 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.ConclusionsContrary 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 registrationClinicalTrials.gov number NCT02163447.

BackgroundCombination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART.MethodsThree hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay.ResultsEstradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases.ConclusionsCombination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority.Clinical trials registrationNCT00993031.

BackgroundIntermittent 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 findingsWe 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.ConclusionsContrary 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 registrationClinicalTrials.gov number NCT02163447.

BackgroundMalaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes.MethodsThis is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants.ResultsThe 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and

BackgroundAngiogenic processes in the placenta are critical regulators of fetal growth and impact birth outcomes, but there are limited data documenting these processes in HIV-infected women or women from low-resource settings.ObjectiveWe sought to determine whether angiogenic factors are associated with adverse birth outcomes in HIV-infected pregnant women started on antiretroviral therapy.Study designThis is a secondary analysis of samples collected as part of a clinical trial randomizing pregnant women and adolescents infected with HIV to lopinavir/ritonavir-based (n = 166) or efavirenz-based (n = 160) antiretroviral therapy in Tororo, Uganda. Pregnant women living with HIV were enrolled between 12-28 weeks of gestation. Plasma samples were evaluated for angiogenic biomarkers (angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin) by enzyme-linked immunosorbent assay between: 16- .05 for all). The incidence of adverse birth outcomes was 16.9% for spontaneous preterm births, 25.6% for small-for-gestational-age births, and 2.8% for stillbirth. We used linear mixed effect modelling to evaluate longitudinal changes in angiogenic factor concentrations between birth outcome groups adjusting for gestational age at venipuncture, maternal age, body mass index, gravidity, and the interaction between treatment arm and gestational age. Two angiogenic factors-soluble endoglin and placental growth factor-were associated with adverse birth outcomes. Significantly higher concentrations of soluble endoglin throughout gestation were found in study participants destined to deliver preterm [likelihood ratio test, χ2(1) = 12.28, P < .0005] and in those destined to have stillbirths [χ2(1) = 5.67, P < .02]. By contrast, significantly lower concentrations of placental growth factor throughout gestation were found in those destined to have small-for-gestational-age births [χ2(1) = 7.89, P < .005] and in those destined to have stillbirths [χ2(1) = 21.59, P < .0001].ConclusionAn antiangiogenic state in the second or third trimester is associated with adverse birth outcomes, including stillbirth in women and adolescents living with HIV and receiving antiretroviral therapy.

BackgroundAngiogenic processes in the placenta are critical regulators of fetal growth and impact birth outcomes, but there are limited data documenting these processes in HIV-infected women or women from low-resource settings.ObjectiveWe sought to determine whether angiogenic factors are associated with adverse birth outcomes in HIV-infected pregnant women started on antiretroviral therapy.Study designThis is a secondary analysis of samples collected as part of a clinical trial randomizing pregnant women and adolescents infected with HIV to lopinavir/ritonavir-based (n = 166) or efavirenz-based (n = 160) antiretroviral therapy in Tororo, Uganda. Pregnant women living with HIV were enrolled between 12-28 weeks of gestation. Plasma samples were evaluated for angiogenic biomarkers (angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin) by enzyme-linked immunosorbent assay between: 16- .05 for all). The incidence of adverse birth outcomes was 16.9% for spontaneous preterm births, 25.6% for small-for-gestational-age births, and 2.8% for stillbirth. We used linear mixed effect modelling to evaluate longitudinal changes in angiogenic factor concentrations between birth outcome groups adjusting for gestational age at venipuncture, maternal age, body mass index, gravidity, and the interaction between treatment arm and gestational age. Two angiogenic factors-soluble endoglin and placental growth factor-were associated with adverse birth outcomes. Significantly higher concentrations of soluble endoglin throughout gestation were found in study participants destined to deliver preterm [likelihood ratio test, χ2(1) = 12.28, P < .0005] and in those destined to have stillbirths [χ2(1) = 5.67, P < .02]. By contrast, significantly lower concentrations of placental growth factor throughout gestation were found in those destined to have small-for-gestational-age births [χ2(1) = 7.89, P < .005] and in those destined to have stillbirths [χ2(1) = 21.59, P < .0001].ConclusionAn antiangiogenic state in the second or third trimester is associated with adverse birth outcomes, including stillbirth in women and adolescents living with HIV and receiving antiretroviral therapy.

BackgroundMalaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes.MethodsThis is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants.ResultsThe 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and

BackgroundLifelong antiretroviral therapy (ART) is recommended for all HIV-infected pregnant women, but early studies suggest that women often drop out of care postpartum and data are limited on virologic outcomes.MethodsWe evaluated viral suppression (primary outcome) and retention in care up to 5 years after ART initiation among HIV-infected women who started lifelong ART during pregnancy, irrespective of CD4 count, in a study in rural Uganda (NCT00993031). Participants were followed in the study for up to 1 year postpartum, then referred to clinics in surrounding communities. A random sample (N = 200) was invited to participate in a cross-sectional follow-up study after completing the trial, involving one visit for a questionnaire and pregnancy and HIV-1 RNA testing. Retention in care was defined as having attended an HIV clinic in the last 90 days. Logistic regression models were used to examine factors associated with viral suppression (HIV-1 RNA

BackgroundIndoor residual spraying of insecticide (IRS) is a key intervention for reducing the burden of malaria in Africa. However, data on the impact of IRS on malaria in pregnancy and birth outcomes is limited.MethodsAn observational study was conducted within a trial of intermittent preventive therapy during pregnancy in Tororo, Uganda. Women were enrolled at 12-20 weeks of gestation between June and October 2014, provided with insecticide-treated bed nets, and followed through delivery. From December 2014 to February 2015, carbamate-containing IRS was implemented in Tororo district for the first time. Exact spray dates were collected for each household. The exposure of interest was the proportion of time during a woman's pregnancy under protection of IRS, with three categories of protection defined: no IRS protection, >0-20 % IRS protection, and 20-43 % IRS protection. Outcomes assessed included malaria incidence and parasite prevalence during pregnancy, placental malaria, low birth weight (LBW), pre-term delivery, and fetal/neonatal deaths.ResultsOf 289 women followed, 134 had no IRS protection during pregnancy, 90 had >0-20 % IRS protection, and 65 had >20-43 % protection. During pregnancy, malaria incidence (0.49 vs 0.10 episodes ppy, P = 0.02) and parasite prevalence (20.0 vs 8.9 %, P 20-43 % IRS protection (1.6 %, P = 0.006). Compared to women with no IRS protection, those with >20-43 % IRS protection had a lower risk of LBW (20.9 vs 3.1 %, P = 0.002), pre-term birth (17.2 vs 1.5 %, P = 0.006), and fetal/neonatal deaths (7.5 vs 0 %, P = 0.03).ConclusionIn this setting, IRS was temporally associated with lower malaria parasite prevalence during pregnancy and at delivery, and improved birth outcomes. IRS may represent an important tool for combating malaria in pregnancy and for improving birth outcomes in malaria-endemic settings. Trial Registration Current Controlled Trials Identifier NCT02163447.

BackgroundIndoor residual spraying of insecticide (IRS) is a key intervention for reducing the burden of malaria in Africa. However, data on the impact of IRS on malaria in pregnancy and birth outcomes is limited.MethodsAn observational study was conducted within a trial of intermittent preventive therapy during pregnancy in Tororo, Uganda. Women were enrolled at 12-20 weeks of gestation between June and October 2014, provided with insecticide-treated bed nets, and followed through delivery. From December 2014 to February 2015, carbamate-containing IRS was implemented in Tororo district for the first time. Exact spray dates were collected for each household. The exposure of interest was the proportion of time during a woman's pregnancy under protection of IRS, with three categories of protection defined: no IRS protection, >0-20 % IRS protection, and 20-43 % IRS protection. Outcomes assessed included malaria incidence and parasite prevalence during pregnancy, placental malaria, low birth weight (LBW), pre-term delivery, and fetal/neonatal deaths.ResultsOf 289 women followed, 134 had no IRS protection during pregnancy, 90 had >0-20 % IRS protection, and 65 had >20-43 % protection. During pregnancy, malaria incidence (0.49 vs 0.10 episodes ppy, P = 0.02) and parasite prevalence (20.0 vs 8.9 %, P 20-43 % IRS protection (1.6 %, P = 0.006). Compared to women with no IRS protection, those with >20-43 % IRS protection had a lower risk of LBW (20.9 vs 3.1 %, P = 0.002), pre-term birth (17.2 vs 1.5 %, P = 0.006), and fetal/neonatal deaths (7.5 vs 0 %, P = 0.03).ConclusionIn this setting, IRS was temporally associated with lower malaria parasite prevalence during pregnancy and at delivery, and improved birth outcomes. IRS may represent an important tool for combating malaria in pregnancy and for improving birth outcomes in malaria-endemic settings. Trial Registration Current Controlled Trials Identifier NCT02163447.

BackgroundIntermittent 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.MethodsWe 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.ResultsThe 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