What-You-See-Is-What-You-Get Computer-Interpretable Guidelines: The Case of NoviGuide Neonatal.

Complex clinical decision support (CDS) that goes beyond representing simple clinical flowcharts to supporting the totality of a care encounter may help improve care quality and consistency. However, integrating a large volume of clinical guidelines applicable to a care encounter poses unique design and safety considerations. We present the visual and technical methods employed in developing NoviGuide, a platform for complex CDS. Assuring safe functioning required transparency of all outputs, which we achieved using a JSON formalism for capturing logic. Unlike raw computer code, logic-as-data can be presented clearly in context to non-informatician reviewers. Two different styles for visualizing CDS logic, random-access and narrative, support different review contexts. We assess the fitness of these solutions for encoding hundreds of neonatal-care guidelines into integrated multi-topic CDS.

Malaria-specific Type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria.

BACKGROUND: Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic region and assess for correlates of protection against MIP. METHODS: We characterised the second trimester cellular immune response among 203 primigravid and multigravid pregnant women enrolled in two clinical trials of chemoprevention in eastern Uganda, utilizing RNA sequencing, flow cytometry, and functional assays. We compared responses across gravidity and determined associations with parasitaemia during pregnancy and placental malaria. FINDINGS: Using whole blood RNA sequencing, no significant differentially expressed genes were identified between primigravid (n = 12) and multigravid (n = 11) women overall (log 2(FC) > 2, FDR < 0.1). However, primigravid (n = 49) women had higher percentages of malaria-specific, non-naïve CD4+ T cells that co-expressed IL-10 and IFNγ compared with multigravid (n = 85) women (p = 0.000023), and higher percentages of these CD4+ T cells were associated with greater risks of parasitaemia in pregnancy (Rs = 0.49, p = 0.001) and placental malaria (p = 0.0073). These IL-10 and IFNγ co-producing CD4+ T cells had a genomic signature of Tr1 cells, including expression of transcription factors cMAF and BATF and cell surface makers CTLA4 and LAG-3. INTERPRETATION: Malaria-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. Understanding whether suppression of Tr1 cells plays a role in naturally acquired gravidity-dependent immunity may aid the development of new vaccines or treatments for MIP. FUNDING: This work was funded by NIH (PO1 HD059454, U01 AI141308, U19 AI089674, U01 AI155325, U01 AI150741), the March of Dimes (Basil O'Connor award), and the Bill and Melinda Gates Foundation (OPP 1113682).

The utilization of clinical decision support tools to identify neonatal hypothermia and its associated risk factors: A prospective observational study.

Hypothermia (axillary temperature less than 36.5°) is a major source of neonatal morbidity and mortality, with a disproportionate burden of disease in low- and middle-income countries. Despite the importance of thermoregulation on newborn outcomes, the global epidemiologic landscape of neonatal hypothermia is poorly characterized. Clinical decision support (CDS) software provides point-of-care recommendations to guide clinical management and may support data capture in settings with limited informatics infrastructure. Towards this end, we conducted a prospective observational study of the NoviGuide, a novel CDS platform for newborn care, at four health facilities in Uganda between September 2022 to May 2021. Data were extracted from clinical information (e.g. axillary temperature, birth weight, gestational age) entered into the NoviGuide by nurses and midwives on newborns within 24 hours of delivery. Descriptive statistics and multivariable logistic regression were used to evaluate neonatal temperature profiles and the association between hypothermia and clinical features. Among 1,027 completed assessments, 30.5% of entries had neonatal hypothermia with significant variation across study sites. On multivariable logistic regression analysis, we found that hypothermia was independently associated with pre-term birth (Adjusted Odd's Ratio [aOR] 2.62, 95% Confidence interval [CI] 1.38-4.98), sepsis/concern for sepsis (aOR 2.73, 95% CI 2.90-3.94), and hypoglycemia/concern for hypoglycemia (aOR 1.78, 95% CI 1.17-2.72). Altogether, neonatal hypothermia was commonly entered into the NoviGuide and associated clinical characteristics aligned with previous studies based on conventional data collection instruments. Our results should be contextualized within unique technical and operational features of CDS tools, including a bias towards acutely ill patients and limited quality control. Nonetheless, this study demonstrates that a CDS used voluntarily by clinicians has the potential to fill key data gaps and drive quality improvement towards reducing neonatal hypothermia in low resource settings.

Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial.

BACKGROUND: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. METHODS: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. RESULTS: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. CONCLUSIONS: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

In Utero Activation of Natural Killer Cells in Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for natural killer (NK) cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero. METHODS: Here, we investigate the impact of congenital CMV infection on the neonatal NK-cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants. RESULTS: We find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56- NK cells, an NK-cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero. CONCLUSIONS: These findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV. CLINICAL TRIALS REGISTRATION: NCT02793622.

Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children.

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84-99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

Peripheral Plasmodium falciparum Infection in Early Pregnancy Is Associated With Increased Maternal Microchimerism in the Offspring.

BACKGROUND: Placental malaria has been associated with increased cord blood maternal microchimerism (MMc), which in turn may affect susceptibility to malaria in the offspring. We sought to determine the impact of maternal peripheral Plasmodium falciparum parasitemia during pregnancy on MMc and to determine whether maternal cells expand during primary parasitemia in the offspring. METHODS: We conducted a nested cohort study of maternal-infant pairs from a prior pregnancy malaria chemoprevention study. Maternal microchimerism was measured by quantitative polymerase chain reaction targeting a maternal-specific marker in genomic DNA from cord blood, first P falciparum parasitemia, and preparasitemia. Logistic and negative binomial regression were used to assess the impact of maternal peripheral parasitemia, symptomatic malaria, and placental malaria on cord blood MMc. Generalized estimating equations were used to assess predictors of MMc during infancy. RESULTS: Early maternal parasitemia was associated with increased detection of cord blood MMc (adjusted odds ratio = 3.91, P = .03), whereas late parasitemia, symptomatic malaria, and placental malaria were not. The first parasitemia episode in the infant was not associated with increased MMc relative to preparasitemia. CONCLUSIONS: Maternal parasitemia early in pregnancy may increase the amount of MMc acquired by the fetus. Future work should investigate the impact of this MMc on immune responses in the offspring.

Implementation of a Newborn Clinical Decision Support Software (NoviGuide) in a Rural District Hospital in Eastern Uganda: Feasibility and Acceptability Study.

BACKGROUND: Lack of trained health care workers and nonadherence to national guidelines are key barriers to achieving high-quality newborn care in health care facilities in low- and middle-income countries. Traditional didactic approaches addressing these barriers fail to account for high staff turnover rates and result in temporary behavior change. NoviGuide, a clinical decision support software designed to standardize neonatal care through point-of-care assessments, has the potential to align bedside practice to national guidelines in settings lacking subspecialty neonatal providers. OBJECTIVE: This study aims to determine the adaptation, adoption, feasibility, acceptability, and sustainability of NoviGuide and its impact on nurse-midwives' knowledge in a rural hospital in eastern Uganda. METHODS: This mixed methods observational study was guided by the Proctor framework. Experts reviewed the clinical content of NoviGuide to ensure fidelity to Uganda guidelines. We enrolled nurses and midwives providing newborn care at Tororo District Hospital, trained them on NoviGuide use, and followed them for 12 months. We assessed adoption, feasibility, acceptability, and sustainability by analyzing NoviGuide use data, comparing it with maternity registry data and administering the System Usability Scale (SUS) and the Center for Health Care Evaluation Provider Satisfaction Questionnaire. We compared the mean knowledge assessment score at baseline, 6 months, and 12 months using a two-tailed t test. RESULTS: Five Ugandan experts suggested two minor changes to NoviGuide: the inclusion of an unsterile birth environment as an indication for empiric antibiotics and the addition of a reminder to follow-up with newborns with temperatures between 37.7°C and 37.9°C. Of the 19 nurse-midwives enrolled in February 2017, 74% (n=14) completed the follow-up in March 2018. The participants entered a total of 1705 assessments of varying newborn characteristics into NoviGuide throughout the day, evening, and night nursing shifts. The SUS score at the end of the study was very high (93.5, above the average of 68). Participants had a positive perception about NoviGuide, reporting that NoviGuide saved time (mean 5, SD 0) and prevented mistakes (mean 5, SD 0), and that they felt more confident in taking care of newborns when they used NoviGuide (mean 5, SD 0). Participants were highly satisfied with NoviGuide (mean 4.86, SD 0.36), although they lacked medical supplies and materials needed to follow NoviGuide recommendations (mean 3.3, SD 1.22). The participants' knowledge scores improved by a mean change of 3.7 (95% CI 2.6-4.8) at 6 months and 6.7 (95% CI 4.6-8.2) at 12 months (P<.001). CONCLUSIONS: NoviGuide was easily adapted to the Uganda guidelines. Nurse-midwives used NoviGuide frequently and reported high levels of satisfaction despite challenges with medical supplies and high staff turnover. NoviGuide improved knowledge and confidence in newborn care without in-person didactic training. NoviGuide use has the potential to scale up quality newborn care by facilitating adherence to national guidelines.

Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy.

The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.

Generation of a malaria negative Ugandan birth weight standard for the diagnosis of small for gestational age.

OBJECTIVE: Placental malaria is a known risk factor for small for gestational age (SGA) neonates. However, currently utilized international and African birthweight standards have not controlled for placental malaria and/or lack obstetrical ultrasound dating. We developed a neonatal birthweight standard based on obstetrically dated pregnancies that excluded individuals with clinical malaria, asymptomatic parasitemia, and placental malaria infection. We hypothesized that current curves underestimate true ideal birthweight and the prevalence of SGA. STUDY DESIGN: Participants were pooled from two double-blind randomized control trials of intermittent preventive therapy during pregnancy in Uganda. HIV-negative women without comorbidities were enrolled from 12-20 weeks gestation. Gestational age was confirmed by ultrasound dating. Women were followed through pregnancy and delivery for clinical malaria, asymptomatic parasitemia, and placental malaria. Women without malaria, asymptomatic parasitemia, or placental malaria formed the malaria negative cohort and generated the Ugandan birthweight standard. The Ugandan standard was then used to estimate the prevalence of SGA neonates in the malaria positive cohort. These findings were compared to international (Williams, World Health Organization (WHO), and INTERGROWTH-21st) and regional standards (Tanzanian and Malawi). RESULTS: 926 women had complete delivery data; 393 (42.4%) met criteria for the malaria negative cohort and 533 (57.6%) were malaria positive. The Ugandan standard diagnosed SGA in 17.1% of malaria positive neonates; similar to the INTERGROWTH-21st and Schmiegelow curves. The WHO curve diagnosed SGA in significantly more neonates (32.1%, p = <0.001), and the Malawi curve diagnosed SGA in significantly fewer neonates (8.3%, p <0.001). CONCLUSION: Exclusion of women with subclinical placental malaria in malaria-endemic areas created birth weight norms at higher values and increased the detection of SGA. Birth weight standards that fail to account for endemic illness may underestimate the true growth potential of healthy neonates.

Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women.

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of >10.3 ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks of gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV coadministration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2,880 mg fixed-dose regimen when provided monthly. (The clinical trials described in this paper have been registered at ClinicalTrials.gov under identifiers NCT02163447 and NCT02282293.).

The impact of gravidity, symptomatology and timing of infection on placental malaria.

BACKGROUND: Placental malaria is associated with increased risk of adverse perinatal outcomes. While primigravidity has been reported as a risk factor for placental malaria, little is known regarding the relationship between gravidity, symptomatology and timing of Plasmodium falciparum infection and the development of placental malaria. METHODS: The aim of this study was to investigate the relationship between the development of placental malaria and gravidity, timing of infection, and presence of symptoms. This is a secondary analysis of data from a double-blind randomized control trial of intermittent preventive therapy during pregnancy in Uganda. Women were enrolled from 12 to 20 weeks gestation and followed through delivery. Exposure to malaria parasites was defined as symptomatic (fever with positive blood smear) or asymptomatic (based on molecular detection of parasitaemia done routinely every 4 weeks). The primary outcome was placental malaria diagnosed by histopathology, placental blood smear, and/or placental blood loop-mediated isothermal amplification. Multivariate analyses were performed using logistic regression models. Subgroup analysis was performed based on the presence of symptomatic malaria, gravidity, and timing of infection. RESULTS: Of the 228 patients with documented maternal infection with malaria parasites during pregnancy, 101 (44.3%) had placental malaria. Primigravidity was strongly associated with placental malaria (aOR 8.90, 95% CI 4.34-18.2, p < 0.001), and each episode of malaria was associated with over a twofold increase in placental malaria (aOR 2.35, 95% CI 1.69-3.26, p < 0.001). Among multigravid women, the odds of placental malaria increased by 14% with each advancing week of gestation at first documented infection (aOR 1.14, 95% CI 1.02-1.27, p = 0.02). When stratified by the presence of symptoms, primigravidity was only associated with placental malaria in asymptomatic women, who had a 12-fold increase in the odds of placental malaria (aOR 12.19, 95% CI 5.23-28.43, p < 0.001). CONCLUSIONS: Total number of P. falciparum infections in pregnancy is a significant predictor of placental malaria. The importance of timing of infection on the development of placental malaria varies based on gravidity. In primigravidas, earlier asymptomatic infections were more frequently identified in those with placental malaria, whereas in multigravidas, parasitaemias detected later in gestation were associated with placental malaria. Earlier initiation of an effective intermittent preventive therapy may help to prevent placental malaria and improve birth outcomes, particularly in primigravid women.

The Impact of Control Interventions on Malaria Burden in Young Children in a Historically High-Transmission District of Uganda: A Pooled Analysis of Cohort Studies from 2007 to 2018.

There is limited evidence on whether malaria elimination is feasible in high-transmission areas of Africa. Between 2007 and 2018, we measured the impact of malaria control interventions in young children enrolled in three clinical trials and two observational studies in Tororo, Uganda, a historically high-transmission area. Data were pooled from children aged 0.5-2 years. Interventions included individually assigned chemoprevention and repeated rounds of indoor residual spraying (IRS) of insecticide. All children received long-lasting insecticidal nets (LLINs) and treatment for symptomatic malaria with artemisinin-based combination therapy. Malaria incidence was measured using passive surveillance and parasite prevalence by microscopy and molecular methods at regular intervals. Poisson's generalized linear mixed-effects models were used to estimate the impact of various control interventions. In total, 939 children were followed over 1,221.7 person years. In the absence of chemoprevention and IRS (reference group), malaria incidence was 4.94 episodes per person year and parasite prevalence 47.3%. Compared with the reference group, implementation of IRS was associated with a 97.6% decrease (95% CI: 93.3-99.1%, P = 0.001) in the incidence of malaria and a 96.0% decrease (95% CI: 91.3-98.2%, P < 0.001) in parasite prevalence (both measured after the fifth and sixth rounds of IRS). The addition of chemoprevention with monthly dihydroartemisinin-piperaquine to IRS was associated with a 99.5% decrease (95% CI: 98.6-99.9%, P < 0.001) in the incidence of malaria. In a historically high-malaria burden area of Uganda, a combination of LLINs, effective case management, IRS, and chemoprevention was associated with almost complete elimination of malaria in young children.

Intermittent preventive treatment with dihydroartemisinin-piperaquine and risk of malaria following cessation in young Ugandan children: a double-blind, randomised, controlled trial.

BACKGROUND: Intermittent 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. METHODS: In 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. FINDINGS: Between 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<0·0001). After cessation of IPT, children who had previously received dihydroartemisinin-piperaquine every 4 weeks had a lower incidence of symptomatic malaria than children who were treated every 12 weeks; 62 episodes occurred among children previously treated every 4 weeks (incidence 0·73 episodes per person-year) compared with 83 episodes among children treated every 12 weeks (incidence 1·1 episodes per person-year; aIRR 0·62, 0·40-0·95, p=0·028). In the 4-week group, 94 (98%) of 96 children had adverse events versus 87 (100%) of 87 children in the 12-week group. The most commonly reported adverse event was cough in both treatment groups (94 [98%] in the 4-week group vs 87 [100%] in the 12-week group). 16 children had severe adverse events (seven [7%] children in the 4-week group vs nine [10%] children in the 12-week group). No severe adverse events were thought to be related to study drug administration. One death occurred during the intervention (age 8 weeks to 24 months), which was due to respiratory failure unrelated to malaria. INTERPRETATION: IPT with dihydroartemisinin-piperaquine given every 4 weeks was superior to treatment every 12 weeks for the prevention of malaria during childhood, and this protection was extended for up to 1 year after cessation of IPT. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins.

Maternal infection during pregnancy can have lasting effects on neurodevelopment, but the impact of malaria in pregnancy on child neurodevelopment is unknown. We present a case of a 24-year-old gravida three woman enrolled at 14 weeks 6 days of gestation in a clinical trial evaluating malaria prevention strategies in pregnancy. She had two blood samples test positive for Plasmodium falciparum using loop-mediated isothermal amplification before 20 weeks of gestation. At 31 weeks 4 days of gestation, the woman presented with preterm premature rupture of membranes, and the twins were delivered by cesarean section. Twin A was 1,920 g and Twin B was 1,320 g. Both placentas tested negative for malaria by microscopy, but the placenta of Twin B had evidence of past malaria by histology. The twins' development was assessed using the Bayley Scales of Infant and Toddler Development-Third Edition. At 1 year chronologic age, Twin B had lower scores across all domains (composite scores: cognitive, Twin A [100], Twin B [70]; motor, Twin A [88], Twin B [73]; language, Twin A [109], Twin B [86]). This effect persisted at 2 years chronologic age (composite scores: cognitive, Twin A [80], Twin B [60]; motor, Twin A [76], Twin B [67]; language, Twin A [77], Twin B [59]). Infant health was similar over the first 2 years of life. We report differences in neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. Additional research is needed to evaluate the impact of placental malaria on neurodevelopmental complications. Trial registration number: ClinicalTrials.gov number, NCT02163447. Registered: June 2014, https://clinicaltrials.gov/ct2/show/NCT02163447.

Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda.

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.).

Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial.

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.

Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine.

Background: Dihydroartemisinin-piperaquine (DHA-PQ) is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine (PQ) exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. Methods: Human immunodeficiency virus-uninfected pregnant women (n = 300) were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks' gestation and randomized to sulfadoxine-pyrimethamine every 8 weeks, DHA-PQ every 8 weeks, or DHA-PQ every 4 weeks during pregnancy. Pharmacokinetic sampling for PQ was performed every 4 weeks, and an intensive pharmacokinetic substudy was performed in 30 women at 28 weeks' gestation. Concentration-effect relationships were assessed between exposure to PQ; the prevalence of Plasmodium falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birth weight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed. Results: Model-defined PQ target venous plasma concentrations of 13.9 ng/mL provided 99% protection from P. falciparum infection during pregnancy. Each 10-day increase in time above target PQ concentrations was associated with reduced odds of placental parasitemia, preterm birth, and low birth weight, though increases in PQ concentrations were associated with QT interval prolongation. Modeling suggests that daily or weekly administration of lower dosages of PQ, compared to standard dosing, will maintain PQ trough levels above target concentrations with reduced PQ peak levels, potentially limiting toxicity. Conclusions: The protective efficacy of IPTp with DHA-PQ was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative DHA-PQ IPTp dosing strategies are warranted. Clinical Trials Registration: NCT02163447.

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz.

Background: A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Methods: Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. Results: PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), <1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and >96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. Conclusions: For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. Clinical Trials Registration: NCT02282293.

Protective Effect of Indoor Residual Spraying of Insecticide on Preterm Birth Among Pregnant Women With HIV Infection in Uganda: A Secondary Data Analysis.

Background: Recent evidence demonstrated improved birth outcomes among human immunodeficiency virus (HIV)-uninfected pregnant women protected by indoor residual spraying of insecticide (IRS). Evidence regarding its impact on HIV-infected pregnant women is lacking. Methods: Data were pooled from 2 studies conducted before and after an IRS campaign in Tororo, Uganda, among HIV-infected pregnant women who received bed nets, daily trimethoprim-sulfamethoxazole, and combination antiretroviral therapy at enrollment. Exposure was the proportion of pregnancy protected by IRS. Adverse birth outcomes included preterm birth, low birth weight, and fetal or neonatal death. Multivariate Poisson regression with robust standard errors was used to estimate risk ratios. Results: Of 565 women in our analysis, 380 (67%), 88 (16%), and 97 (17%) women were protected by IRS for 0%, >0% to 90%, and >90% of their pregnancy, respectively. Any IRS protection significantly reduced malaria incidence during pregnancy and placental malaria risk. Compared with no IRS protection, >90% IRS protection reduced preterm birth risk (risk ratio, 0.35; 95% confidence interval, .15-.84), with nonsignificant decreases in the risk of low birth weight (0.68; .29-1.57) and fetal or neonatal death (0.24; .04-1.52). Discussion: Our exploratory analyses support the hypothesis that IRS may significantly reduce malaria and preterm birth risk among pregnant women with HIV receiving bed nets, daily trimethoprim-sulfamethoxazole, and combination antiretroviral therapy.