Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women.

BACKGROUND: Malaria and HIV infection overlap geographically in sub-Saharan Africa and share risk factors. HIV infection increases malaria's severity, especially in pregnant women. The World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for pregnant women living in areas of stable malaria transmission. However, HIV-positive women on daily cotrimoxazole prophylaxis (recommended for prevention of opportunistic infections in people with HIV) cannot receive SP due to adverse drug interactions, so malaria prevention in this vulnerable population currently relies on daily cotrimoxazole prophylaxis alone. This review is based on a new protocol and provides an update to the 2011 Cochrane Review that evaluated alternative drugs for IPTp to prevent malaria in HIV-positive women. OBJECTIVES: To compare the safety and efficacy of intermittent preventive treatment regimens for malaria prevention in HIV-positive pregnant women. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registries to 31 January 2024. To identify relevant additional studies or unpublished work, we checked references and contacted study authors and other researchers working on malaria and HIV. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing any intermittent preventive treatment regimen for preventing malaria in HIV-positive pregnant women against daily cotrimoxazole prophylaxis alone, placebo, current or previous standard of care, or combinations of these options. By 'standard of care' we refer to the country's recommended drug regimen to prevent malaria in pregnancy among HIV-positive women, or the treatment that a trial's research team considered to be the standard of care. DATA COLLECTION AND ANALYSIS: Review authors, in pairs, independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias in included trials, and extracted data. We contacted trial authors when additional information was required. We presented dichotomous outcomes using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes as mean differences (MDs). We presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach for what we considered to be the main comparisons and outcomes. MAIN RESULTS: We included 14 RCTs, with a total of 4976 HIV-positive pregnant women initially randomized. All trials assessed the efficacy and safety of one antimalarial used as IPTp (mefloquine, dihydroartemisinin/piperaquine, SP, or azithromycin) with or without daily cotrimoxazole, compared to daily cotrimoxazole alone, placebo, or a standard of care regimen. We grouped the trials into nine comparisons. Our main comparison evaluated the current standard of care (daily cotrimoxazole) with another drug regimen (mefloquine or dihydroartemisinin/piperaquine) versus daily cotrimoxazole with or without placebo. In this comparison, two trials evaluated mefloquine and three evaluated dihydroartemisinin/piperaquine. We conducted meta-analyses that included trials evaluating dihydroartemisinin/piperaquine plus cotrimoxazole, and trials that evaluated mefloquine plus cotrimoxazole, as we considered there to be no qualitative or quantitative heterogeneity among trials for most outcomes. We considered drug-related adverse events and HIV-related outcomes to be drug-specific. Daily cotrimoxazole prophylaxis plus another drug regimen (mefloquine or dihydroartemisinin/piperaquine) probably results in lower risk of maternal peripheral parasitaemia at delivery (RR 0.62, 95% CI 0.41 to 0.95; 2406 participants, 5 trials; moderate-certainty evidence). It results in little or no difference in maternal anaemia cases at delivery (RR 0.98, 95% CI 0.90 to 1.07; 2417 participants, 3 trials; high-certainty evidence). It probably results in a decrease in placental malaria measured by blood smear (RR 0.54, 95% CI 0.31 to 0.93; 1337 participants, 3 trials; moderate-certainty evidence), and probably results in little or no difference in low birth weight (RR 1.16, 95% CI 0.95 to 1.41; 2915 participants, 5 trials; moderate-certainty evidence). There is insufficient evidence to ascertain whether daily cotrimoxazole prophylaxis plus another drug regimen affects the risk of cord blood parasitaemia (RR 0.27, 95% CI 0.04 to 1.64; 2696 participants, 5 trials; very low-certainty evidence). Daily cotrimoxazole prophylaxis plus another drug regimen probably results in little or no difference in foetal loss (RR 1.03, 95% CI 0.73 to 1.46; 2957 participants, 5 trials; moderate-certainty evidence), and may result in little or no difference in neonatal mortality (RR 1.21, 95% CI 0.68 to 2.14; 2706 participants, 4 trials; low-certainty evidence). Due to the probability of an increased risk of mother-to-child HIV transmission and some adverse drug effects noted with mefloquine, we also looked at the results for dihydroartemisinin/piperaquine specifically. Dihydroartemisinin/piperaquine plus daily contrimoxazole probably results in little to no difference in maternal peripheral parasitaemia (RR 0.59, 95% CI 0.31 to 1.11; 1517 participants, 3 trials; moderate-certainty evidence) or anaemia at delivery (RR 0.95, 95% CI 0.82 to 1.10; 1454 participants, 2 trials; moderate-certainty evidence), but leads to fewer women having placental malaria when measured by histopathologic analysis (RR 0.67, 95% CI 0.50 to 0.90; 1570 participants, 3 trials; high-certainty evidence). The addition of dihydroartemisinin/piperaquine to daily cotrimoxazole probably made little to no difference to rates of low birth weight (RR 1.13, 95% CI 0.87 to 1.48; 1695 participants, 3 trials), foetal loss (RR 1.14, 95% CI 0.68 to 1.90; 1610 participants, 3 trials), or neonatal mortality (RR 1.03, 95% CI 0.39 to 2.72; 1467 participants, 2 trials) (all moderate-certainty evidence). We found low-certainty evidence of no increased risk of gastrointestinal drug-related adverse events (RR 1.42, 95% CI 0.51 to 3.98; 1447 participants, 2 trials) or mother-to-child HIV transmission (RR 1.54, 95% CI 0.26 to 9.19; 1063 participants, 2 trials). AUTHORS' CONCLUSIONS: Dihydroartemisinin/piperaquine and mefloquine added to daily cotrimoxazole seem to be efficacious in preventing malaria infection in HIV-positive pregnant women compared to daily cotrimoxazole alone. However, increased risk of HIV transmission to the foetus and poor drug tolerability may be barriers to implementation of mefloquine in practice. In contrast, the evidence suggests that dihydroartemisinin/piperaquine does not increase the risk of HIV mother-to-child transmission and is well tolerated.

Birth outcomes and survival by sex among newborns and children under 2 in the Birhan Cohort: a prospective cohort study in the Amhara Region of Ethiopia.

INTRODUCTION: Despite the progress in reducing child mortality, the rate remains high, particularly in sub-Saharan African countries. Limited data exist on child survival and other birth outcomes by sex. This study compared survival rates and birth outcomes by sex among neonates and children under 2 in Ethiopia. METHODS: Women who gave birth after 28 weeks of gestation and their newborns were included in the analysis. Survival probabilities were estimated for males and females in the neonatal period as well as the 2-year period following birth using Kaplan-Meier curves. HRs and 95% CIs were compared between males and females under 2. Descriptive statistics and χ2 tests were used to determine the sex-disaggregated variation in the birth outcomes of preterm birth, low birth weight (LBW), stillbirth, small for gestational age (SGA) and large for gestational age (LGA). RESULTS: The study included a total of 3904 women and child pairs. The neonatal mortality rate for males (3.4%, 95% CI 2.6% to 4.2%) was higher compared with females (1.7%, 95% CI 1.1% to 2.3%). The hazard of death during the first 28 days of life was approximately two times higher for males compared with females (HR 1.99, 95% CI 1.30 to 3.06) but was not significantly different after this period. While there was a non-significant difference between males and females in the proportion of preterm, LBW and LGA births, we found a significantly higher proportion of stillbirth (2.7% vs 1.3%, p=0.003) and SGA (20.5% vs 15.6%, p<0.001) for males compared with females. CONCLUSIONS: This study identified a significant sex difference in mortality and birth outcomes. We recommend focusing future research on the mechanisms of these sex differences in order to better design intervention programmes to reduce disparities and improve outcomes for neonates.

Estimates and determinants of health facility delivery in the Birhan cohort in Ethiopia.

Health facility delivery is one of the critical indicators to monitor progress towards the provision of skilled delivery care and reduction in perinatal mortality. In Ethiopia, utilization of health facilities for skilled delivery care has been increasing but varies greatly by region and among specific socio-demography groups. We aimed to measure the prevalence and determinants of health facility delivery in the Amhara region in Ethiopia. From December 2018 to November 2020, we conducted a longitudinal study from a cohort of 2801 pregnant women and described the location of delivery and the association with determinants. We interviewed a subset of women who delivered in the community and analyzed responses using the three delays model to understand reasons for not using health facility services. A multivariable poisson regression model with robust error variance was used to estimate the presence and magnitude of association between location of delivery and the determinants. Of the 2,482 pregnant women followed through to birth, 73.6% (n = 1,826) gave birth in health facilities, 24.3% (n = 604) gave birth at home and 2.1% (n = 52) delivered on the way to a health facility. Determinants associated with increased likelihood of delivery at a health facility included formal maternal education, shorter travel times to health facilities, primiparity, higher wealth index and having attended at least one ANC visit. Most common reasons mothers gave for not delivering in a health facility were delays in individual/family decision to seek care. The proportion of deliveries occurring in health facilities is increasing but falls below targets. Interventions that focus on the identified social-demographic determinants and delays are warranted.

Efficacy and safety of hydroxychloroquine for treatment of mild SARS-CoV-2 infection and prevention of COVID-19 severity in pregnant and postpartum women: A randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Pregnant women have an increased risk of severe COVID-19. Evaluation of drugs with a safety reproductive toxicity profile is a priority. At the beginning of the pandemic, hydroxychloroquine (HCQ) was recommended for COVID-19 treatment. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted in eight teaching hospitals in Spain to evaluate the safety and efficacy of HCQ in reducing viral shedding and preventing COVID-19 progression. Pregnant and postpartum women with a positive SARS-CoV-2 PCR (with or without mild COVID-19 signs/symptoms) and a normal electrocardiogram were randomized to receive either HCQ orally (400 mg/day for 3 days and 200 mg/day for 11 days) or placebo. PCR and electrocardiogram were repeated at day 21 after treatment start. Enrollment was stopped before reaching the target sample due to low recruitment rate. Trial registration EudraCT #: 2020-001587-29, on April 2, 2020. CLINICAL TRIALS: gov # NCT04410562, registered on June 1, 2020. RESULTS: A total of 116 women (75 pregnant and 41 post-partum) were enrolled from May 2020 to June 2021. The proportion of women with a positive SARS-CoV-2 PCR at day 21 was lower in the HCQ group (21.8%, 12/55) than in the placebo group (31.6%, 18/57), although the difference was not statistically significant (P = 0.499). No differences were observed in COVID-19 progression, adverse events, median change in QTc, hospital admissions, preeclampsia or poor pregnancy and perinatal outcomes between groups. CONCLUSIONS: HCQ was found to be safe in pregnant and postpartum women with asymptomatic or mild SARS-CoV-2 infection. Although the prevalence of infection was decreased in the HCQ group, the statistical power was insufficient to confirm the potential beneficial effect of HCQ for COVID-19 treatment.

Antenatal care coverage in a low-resource setting: Estimations from the Birhan Cohort.

Antenatal care (ANC) coverage estimates commonly rely on self-reported data, which may carry biases. Leveraging prospectively collected longitudinal data from the Birhan field site and its pregnancy and birth cohort, the Birhan Cohort, this study aimed to estimate the coverage of ANC, minimizing assumptions and biases due to self-reported information and describing retention patterns in ANC in rural Amhara, Ethiopia. The study population were women enrolled and followed during pregnancy between December 2018 and April 2020. ANC visits were measured by prospective facility chart abstraction and self-report at enrollment. The primary study outcomes were the total number of ANC visits attended during pregnancy and the coverage of at least one, four, or eight ANC visits. Additionally, we estimated ANC retention patterns. We included 2069 women, of which 150 (7.2%) women enrolled <13 weeks of gestation with complete prospective facility reporting. Among these 150 women, ANC coverage of at least one visit was 97.3%, whereas coverage of four visits or more was 34.0%. Among all women, coverage of one ANC visit was 92.3%, while coverage of four or more visits was 28.8%. No women were found to have attended eight or more ANC visits. On retention in care, 70.3% of participants who had an ANC visit between weeks 28 and <36 of gestation did not return for a subsequent visit. Despite the high proportion of pregnant women who accessed ANC at least once in our study area, the coverage of four visits remains low. Further efforts are needed to enhance access to more ANC visits, retain women in care, and adhere to the most recent Ethiopian National ANC guideline of at least eight ANC visits. It is essential to identify the factors that lead a large proportion of women to discontinue ANC follow-up.

Prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation.

BACKGROUND: The effectiveness of community delivery of intermittent preventive treatment (C-IPT) of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine has been evaluated in selected areas of the Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria. We aimed to assess the effect of C-IPTp on the potential development of Plasmodium falciparum resistance to sulfadoxine-pyrimethamine, since it could threaten the effectiveness of this strategy. METHODS: Health facility-based cross-sectional surveys were conducted at baseline and 3 years after C-IPTp implementation in two neighbouring areas per country, one with C-IPTp intervention, and one without, in the four project countries. Dried blood spots from children under five years of age with clinical malaria were collected. Sulfadoxine-pyrimethamine resistance-associated mutations of the P falciparum dhfr (Asn51Ile/Cys59Arg/Ser108Asn/Ile164Leu) and dhps (Ile431Val/Ser436Ala/Ala437Gly/Lys540Glu/Ala581Gly/Ala613Ser) genes were analysed. FINDINGS: 2536 children were recruited between June 19 and Oct 10, 2018, during baseline surveys. Endline surveys were conducted among 2447 children between July 26 and Nov 30, 2021. In the Democratic Republic of the Congo, the dhfr/dhps IRNI/ISGEAA inferred haplotype remained lower than 10%, from 2% (5 of 296) at baseline to 8% (24 of 292) at endline, and from 3% (9 of 300) at baseline to 6% (18 of 309) at endline surveys in intervention and non-intervention areas respectively with no significant difference in the change between the areas. In Mozambique, the prevalence of this haplotype remained stable at over 60% (194 [64%] of 302 at baseline to 194 [64%] of 303 at endline, and 187 [61%] of 306 at baseline to 183 [61%] of 301 in endline surveys, in non-intervention and intervention areas respectively). No isolates harbouring the dhps ISGEAA genotype were found in Nigeria. In Madagascar, only five isolates with this haplotype were found in the non-intervention area (2 [>1%] of 300 at baseline and 3 [1%] of 300 at endline surveys). No isolates were found carrying the dhps ISGEGA genotype. INTERPRETATION: C-IPTp did not increase the prevalence of molecular markers associated with sulfadoxine-pyrimethamine resistance after three years of programme implementation. These findings reinforce C-IPTp as a strategy to optimise the control of malaria during pregnancy, and support the WHO guidelines for prevention of malaria in pregnancy. FUNDING: UNITAID [2017-13-TIPTOP].

Cost-effectiveness of community-based distribution of intermittent preventive treatment of malaria in pregnancy in Madagascar, Mozambique, Nigeria, and the Democratic Republic of Congo.

INTRODUCTION: Malaria in pregnancy is a major driver of maternal and infant mortality in sub-Saharan Africa. The WHO recommends the administration of intermittent preventive treatment with sulfadoxine pyrimethamine (IPTp-SP) at antenatal care (ANC) visits. Despite being a highly cost-effective strategy, IPTp-SP coverage and uptake remains low. A pilot project was conducted to assess the cost-effectiveness (CE) of community-based delivery of IPTp (C-IPTp) in addition to ANC delivery to increase IPTp uptake in the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA). METHODS: Costs and CE estimates of C-IPTp were calculated according to two scenarios: (1) costs in 'programmatic mode' (ie, costs if C-IPTp was to be implemented by national health systems) and (2) costs from the pilot project. The effectiveness of C-IPTp was obtained through estimates of the averted disability-adjusted life-years (DALYs) associated with maternal clinical malaria and anaemia, low birth weight and neonatal mortality. RESULTS: Net incremental costs of C-IPTp ranged between US$6138-US$47 177 (DRC), US$5552-US$31 552 (MDG), US$10 202-US$53 221 (MOZ) and US$667-US$28 645 (NGA) per 1000 pregnant women, under scenarios (1) and (2), respectively. Incremental cost-effectiveness ratios (ICERs) ranged between US$15-US$119 in DRC, US$9-US$53 in MDG, US$104-US$543 in MOZ and US$2-US$66 in NGA per DALY averted, under scenarios (1) and (2), respectively. ICERs fall below the WHO recommended CE threshold based on the gross domestic product per capita. CONCLUSION: Findings suggest that C-IPTp is a highly cost-effective intervention. Results can inform policy decisions on adopting and optimising effective interventions for preventing malaria in pregnancy.

The economic costs of malaria in pregnancy: evidence from four sub-Saharan countries.

Background Malaria in pregnancy is a major public health problem in sub-Saharan Africa (SSA), which imposes a significant economic burden. We provide evidence on the costs of malaria care in pregnancy to households and the health system in four high-burden countries in SSA.  Methods Household and health system economic costs associated with malaria control in pregnancy were estimated in selected areas of the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA). An exit survey was administered to 2,031 pregnant women when leaving the antenatal care (ANC) clinic from October 2020 to June 2021. Women reported the direct and indirect costs associated to malaria prevention and treatment in pregnancy. To estimate health system costs, we interviewed health workers from 133 randomly selected health facilities. Costs were estimated using an ingredients-based approach. Results Average household costs of malaria prevention per pregnancy were USD6.33 in DRC, USD10.06 in MDG, USD15.03 in MOZ and USD13.33 in NGA. Household costs of treating an episode of uncomplicated/complicated malaria were USD22.78/USD46 in DRC, USD16.65/USD35.65 in MDG, USD30.54/USD61.25 in MOZ and USD18.92/USD44.71 in NGA, respectively. Average health system costs of malaria prevention per pregnancy were USD10.74 in DRC, USD16.95 in MDG, USD11.17 in MOZ and USD15.64 in NGA. Health system costs associated with treating an episode of uncomplicated/complicated malaria were USD4.69/USD101.41 in DRC, USD3.61/USD63.33 in MDG, USD4.68/USD83.70 in MOZ and USD4.09/USD92.64 in NGA. These estimates resulted in societal costs of malaria prevention and treatment per pregnancy of USD31.72 in DRC, USD29.77 in MDG, USD31.98 in MOZ and USD46.16 in NGA. Conclusions Malaria in pregnancy imposes a high economic burden on households and the health system. Findings emphasize the importance of investing in effective strategies that improve access to malaria control and reduce the burden of the infection in pregnancy.

Development of Prediction Models for Antenatal Care Attendance in Amhara Region, Ethiopia.

Importance: Antenatal care prevents maternal and neonatal deaths and improves birth outcomes. There is a lack of predictive models to identify pregnant women who are at high risk of failing to attend antenatal care in low-resource settings. Objective: To develop a series of predictive models to identify women who are at high risk of failing to attend antenatal care in a rural setting in Ethiopia. Design, Setting, and Participants: This prognostic study used data from the Birhan Health and Demographic Surveillance System and its associated pregnancy and child cohort. The study was conducted at the Birhan field site, North Shewa zone, Ethiopia, a platform for community- and facility-based research and training, with a focus on maternal and child health. Participants included women enrolled during pregnancy in the pregnancy and child cohort between December 2018 and March 2020, who were followed-up in home and facility visits. Data were analyzed from April to December 2022. Exposures: A wide range of sociodemographic, economic, medical, environmental, and pregnancy-related factors were considered as potential predictors. The selection of potential predictors was guided by literature review and expert knowledge. Main Outcomes and Measures: The outcome of interest was failing to attend at least 1 antenatal care visit during pregnancy. Prediction models were developed using logistic regression with regularization via the least absolute shrinkage and selection operator and ensemble decision trees and assessed using the area under the receiving operator characteristic curve (AUC). Results: The study sample included 2195 participants (mean [SD] age, 26.8 [6.1] years; mean [SD] gestational age at enrolment, 25.5 [8.8] weeks). A total of 582 women (26.5%) failed to attend antenatal care during cohort follow-up. The AUC was 0.61 (95% CI, 0.58-0.64) for the regularized logistic regression model at conception, with higher values for models predicting at weeks 13 (AUC, 0.68; 95% CI, 0.66-0.71) and 24 (AUC, 0.66; 95% CI, 0.64-0.69). AUC values were similar with slightly higher performance for the ensembles of decision trees (conception: AUC, 0.62; 95% CI, 0.59-0.65; 13 weeks: AUC, 0.70; 95% CI, 0.67-0.72; 24 weeks: AUC, 0.67; 95% CI, 0.64-0.69). Conclusions and Relevance: This prognostic study presents a series of prediction models for antenatal care attendance with modest performance. The developed models may be useful to identify women at high risk of missing their antenatal care visits to target interventions to improve attendance rates. This study opens the possibility to develop and validate easy-to-use tools to project health-related behaviors in settings with scarce resources.

Development of risk prediction models for preterm delivery in a rural setting in Ethiopia.

Background: Preterm birth complications are the leading causes of death among children under five years. However, the inability to accurately identify pregnancies at high risk of preterm delivery is a key practical challenge, especially in resource-constrained settings with limited availability of biomarkers assessment. Methods: We evaluated whether risk of preterm delivery can be predicted using available data from a pregnancy and birth cohort in Amhara region, Ethiopia. All participants were enrolled in the cohort between December 2018 and March 2020. The study outcome was preterm delivery, defined as any delivery occurring before week 37 of gestation regardless of vital status of the foetus or neonate. A range of sociodemographic, clinical, environmental, and pregnancy-related factors were considered as potential inputs. We used Cox and accelerated failure time models, alongside decision tree ensembles to predict risk of preterm delivery. We estimated model discrimination using the area-under-the-curve (AUC) and simulated the conditional distributions of cervical length (CL) and foetal fibronectin (FFN) to ascertain whether they could improve model performance. Results: We included 2493 pregnancies; among them, 138 women were censored due to loss-to-follow-up before delivery. Overall, predictive performance of models was poor. The AUC was highest for the tree ensemble classifier (0.60, 95% confidence interval = 0.57-0.63). When models were calibrated so that 90% of women who experienced a preterm delivery were classified as high risk, at least 75% of those classified as high risk did not experience the outcome. The simulation of CL and FFN distributions did not significantly improve models' performance. Conclusions: Prediction of preterm delivery remains a major challenge. In resource-limited settings, predicting high-risk deliveries would not only save lives, but also inform resource allocation. It may not be possible to accurately predict risk of preterm delivery without investing in novel technologies to identify genetic factors, immunological biomarkers, or the expression of specific proteins.

The impact of community delivery of intermittent preventive treatment of malaria in pregnancy on its coverage in four sub-Saharan African countries (Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria): a quasi-experimental multicentre evaluation.

BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine is recommended at each antenatal care clinic visit in high-moderate transmission areas. However, its coverage remains unacceptably low in many countries. Community health workers can effectively deliver malaria preventive interventions. The aim of this study was to assess the effect of community delivery of IPTp (C-IPTp) on antenatal care and IPTp coverage. METHODS: A community-based IPTp administration approach was implemented in four sub-Saharan countries: the Democratic Republic of the Congo (DR Congo), Madagascar, Mozambique, and Nigeria. A quasi-experimental before and after evaluation by cluster sampling was designed where C-IPTp was implemented in selected country areas in different phases. Baseline (before C-IPTp implementation), midline, and endline household surveys were carried out to assess IPTp intake in pregnant women in 2018, 2019, and 2021. Eligible participants of the household survey were women of reproductive age (13-50 years old, depending on the country) that had a pregnancy that ended (any pregnancy regardless of pregnancy outcome) in the 6 months before the interview. For the first baseline surveys, the target population was women who had a pregnancy that ended in the 12 months before the interview. The primary outcome from the household surveys was the proportion of women who reported having received at least three doses of IPTp during pregnancy. The trial is registered at ClinicalTrials.gov, NCT03600844. FINDINGS: A total of 32 household surveys were conducted between March 15, and Oct 30, 2018, and data from 18 215 interviewed women were analysed. The coverage of at least three doses of IPTp (IPTp3+) increased after the first year of C-IPTp implementation in all project areas in DR Congo (from 22·5% [170/755] to 31·8% [507/1596]), Madagascar (from 17·7% [101/572] to 40·8% [573/1404]), and Nigeria (from 12·7% [130/1027] to 35·2% [423/1203]), with increases between 145·6% (Madagascar) and 506·6% (Nigeria). IPTp3+ coverage increased between baseline and endline in all districts, except for Murrupula (Mozambique) and ranged between 9·6% and 533·6%. This pattern was similar in DR Congo, Madagascar, and Nigeria, and in Mozambique, the increase was lower than the other countries. Antenatal care attendance did not change or increased lightly in all study countries. INTERPRETATION: C-IPTp was associated with an increase in IPTp uptake without reducing antenatal care attendance. The strategy might be considered for malaria control in pregnancy. FUNDING: UNITAID [2017-13-TIPTOP].

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

BACKGROUND: Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria sTo examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (inclu

Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials.

BACKGROUND: Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy-parasitaemia and clinical disease-than adult women. METHODS AND FINDINGS: An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian-Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value < 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value < 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data-12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. CONCLUSIONS: In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant.

Drugs for Intermittent Preventive Treatment of Malaria in Pregnancy: Current Knowledge and Way Forward.

Malaria infection during pregnancy is an important driver of maternal and neonatal health in endemic countries. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention at each scheduled antenatal care visit, starting at the second trimester, in areas of high and moderate transmission. However, the increased resistance to SP in some endemic areas challenges its effectiveness. Furthermore, SP is contraindicated in the first trimester of pregnancy and in HIV-infected women on co-trimoxazole prophylaxis due to potential drug-drug interactions. Thus, in recent last decades, several studies evaluated alternative drugs that could be used for IPTp. A comprehensive literature review was conducted to summarize the evidence on the efficacy and safety of antimalarial drugs being evaluated for IPTp. Chloroquine, amodiaquine, mefloquine and azithromycin as IPTp have proven to be worse tolerated than SP. Mefloquine was found to increase the risk of mother-to-child transmission of HIV. Dihydroartemisin-piperaquine currently constitutes the most promising IPTp drug alternative; it reduced the prevalence of malaria infection, and placental and clinical malaria in studies among HIV-uninfected women, and it is currently being tested in HIV-infected women. Research on effective antimalarial drugs that can be safely administered for prevention to pregnant women should be prioritized. Malaria prevention in the first trimester of gestation and tailored interventions for HIV-infected women remain key research gaps to be addressed.

Evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women: protocol of a multicentre, two-arm, randomised, placebo-controlled, superiority clinical trial (MAMAH project).

INTRODUCTION: Malaria infection during pregnancy is an important driver of maternal and neonatal health especially among HIV-infected women. Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine is recommended for malaria prevention in HIV-uninfected women, but it is contraindicated in those HIV-infected on cotrimoxazole prophylaxis (CTXp) due to potential adverse effects. Dihydroartemisinin-piperaquine (DHA-PPQ) has been shown to improve antimalarial protection, constituting a promising IPTp candidate. This trial's objective is to determine if monthly 3-day IPTp courses of DHA-PPQ added to daily CTXp are safe and superior to CTXp alone in decreasing the proportion of peripheral malaria parasitaemia at the end of pregnancy. METHODS AND ANALYSIS: This is a multicentre, two-arm, placebo-controlled, individually randomised trial in HIV-infected pregnant women receiving CTXp and antiretroviral treatment. A total of 664 women will be enrolled at the first antenatal care clinic visit in sites from Gabon and Mozambique. Participants will receive an insecticide-treated net, and they will be administered monthly IPTp with DHA-PPQ or placebo (1:1 ratio) as directly observed therapy from the second trimester of pregnancy. Primary study outcome is the prevalence of maternal parasitaemia at delivery. Secondary outcomes include prevalence of malaria-related maternal and infant outcomes and proportion of adverse perinatal outcomes. Participants will be followed until 6 weeks after the end of pregnancy and their infants until 1 year of age to also evaluate the impact of DHA-PPQ on mother-to-child transmission of HIV. The analysis will be done in the intention to treat and according to protocol cohorts, adjusted by gravidity, country, seasonality and other variables associated with malaria. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the institutional and national ethics committees of Gabon and Mozambique and the Hospital Clinic of Barcelona. Project results will be presented to all stakeholders and published in open-access journals. TRIAL REGISTRATION NUMBER: NCT03671109.

Acceptability of Clinical Trials on COVID-19 during Pregnancy among Pregnant Women and Healthcare Providers: A Qualitative Study.

Participation of pregnant women in clinical trials entails challenges mainly related to concerns about the risks for fetuses. We undertook a qualitative study from June to October 2020 to assess the acceptability of participating in COVID-19 clinical trials among pregnant women in Spain. Phenomenology and grounded theory were used as methodological approaches. Semi-structured interviews were conducted with 24 pregnant women and six healthcare providers. Women were unsure if pregnancy was a risk factor to acquire the infection or to develop severe disease and expressed the limited information they had received, which led to uncertainties and emotional suffering. They had concerns regarding participation in clinical trials on COVID-19, regardless of the drug under study. Healthcare providers alluded to the importance of involving pregnant women's relatives at the recruitment visit of the clinical trial. These findings may be useful to facilitate pregnant women's participation in clinical trials.

Adolescent, Pregnant, and HIV-Infected: Risk of Adverse Pregnancy and Perinatal Outcomes in Young Women from Southern Mozambique.

Sub-Saharan Africa concentrates the burden of HIV and the highest adolescent fertility rates. However, there is limited information about the impact of the interaction between adolescence and HIV infection on maternal health in the region. Data collected prospectively from three clinical trials conducted between 2003 and 2014 were analysed to evaluate the association between age, HIV infection, and their interaction, with the risk of maternal morbidity and adverse pregnancy and perinatal outcomes in women from southern Mozambique. Logistic regression and negative binomial models were used. A total of 2352 women were included in the analyses; 31% were adolescents (≤19 years) and 29% HIV-infected women. The effect of age on maternal morbidity and pregnancy and perinatal adverse outcomes was not modified by HIV status. Adolescence was associated with an increased incidence of hospital admissions (IRR 0.55, 95%CI 0.37-0.80 for women 20-24 years; IRR 0.60, 95%CI 0.42-0.85 for women >25 years compared to adolescents; p-value < 0.01) and outpatient visits (IRR 0.86, 95%CI 0.71-1.04; IRR 0.76, 95%CI 0.63-0.92; p-value = 0.02), and an increased likelihood of having a small-for-gestational age newborn (OR 0.50, 95%CI 0.38-0.65; OR 0.43, 95%CI 0.34-0.56; p-value < 0.001), a low birthweight (OR 0.40, 95%CI 0.27-0.59; OR 0.37, 95%CI 0.26-0.53; p-value <0.001) and a premature birth (OR 0.42, 95%CI 0.24-0.72; OR 0.51, 95%CI 0.32-0.82; p-value < 0.01). Adolescence was associated with an increased risk of poor morbidity, pregnancy and perinatal outcomes, irrespective of HIV infection. In addition to provision of a specific maternity care package for this vulnerable group interventions are imperative to prevent adolescent pregnancy.

Community delivery of malaria intermittent preventive treatment in pregnancy: protocol of a quasi-experimental evaluation through multistage cluster sampling household surveys in four sub-Saharan African countries.

BACKGROUND: In sub-Saharan Africa (SSA), millions of pregnant women are exposed to malaria infection. The cornerstone of the WHO strategy to prevent malaria in pregnancy in moderate to high-transmission areas is the administration of intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine at each scheduled antenatal care (ANC) visit. However, overall coverage remains low. 'Transforming IPT for Optimal Pregnancy' (TIPTOP) project aims at delivering IPTp at the community level (C-IPTp) to complement ANC provision with the goal of increasing IPTp coverage and improving maternal and infant's health. This protocol describes the approach to measure the effect of this strategy through household surveys (HHS) in four SSA countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria. METHODS AND ANALYSIS: A quasi-experimental evaluation has been designed. Delivery of C-IPTp will start first in one area per country, and later it will be extended to two more areas per country. HHS will be carried out before C-IPTp implementation in all study sites, at midterm in initial implementation areas, and after the implementation in all project areas. A multistage cluster sampling method will be followed for the selection of participants. Women of reproductive age who had a pregnancy that ended in the 6 or 12 months prior to the interview, depending on the survey, will be invited to participate by responding to a questionnaire. The main indicators will be coverage of three or more doses of IPTp and attendance to at least four ANC visits. A difference-in-difference analysis will be performed to evaluate the effectiveness of C-IPTp. ETHICS AND DISSEMINATION: The project has been reviewed by the ethics committees of WHO, Hospital Clinic of Barcelona and all project country boards. Project results will be disseminated to in-country stakeholders and at regional and international meetings. TIPTOP project aims to develop and disseminate global recommendations for C-IPTp delivery. TRIAL REGISTRATION NUMBER: NCT03600844; Pre-results.

Coverage of intermittent preventive treatment of malaria in pregnancy in four sub-Saharan countries: findings from household surveys.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is a key malaria prevention strategy in areas with moderate to high transmission. As part of the TIPTOP (Transforming IPT for Optimal Pregnancy) project, baseline information about IPTp coverage was collected in eight districts from four sub-Saharan countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria. METHODS: Cross-sectional household surveys were conducted using a multistage cluster sampling design to estimate the coverage of IPTp and antenatal care attendance. Eligible participants were women of reproductive age who had ended a pregnancy in the 12 months preceding the interview and who had resided in the selected household during at least the past 4 months of pregnancy. Coverage was calculated using percentages and 95% confidence intervals. RESULTS: A total of 3911 women were interviewed from March to October 2018. Coverage of at least three doses of IPTp (IPTp3+) was 22% and 24% in DRC project districts; 23% and 12% in Madagascar districts; 11% and 16% in Nigeria local government areas; and 63% and 34% in Mozambique districts. In DRC, Madagascar and Nigeria, more than two-thirds of women attending at least four antenatal care visits during pregnancy received less than three doses of IPTp. CONCLUSIONS: The IPTp3+ uptake in the survey districts was far from the universal coverage. However, one of the study districts in Mozambique showed a much higher coverage of IPTp3+ than the other areas, which was also higher than the 2018 average national coverage of 41%. The reasons for the high IPTp3+ coverage in this Mozambican district are unclear and require further study.