Efficacy and safety of pyronaridine-artesunate (PYRAMAX) for the treatment of P. falciparum uncomplicated malaria in African pregnant women (PYRAPREG): study protocol for a phase 3, non-inferiority, randomised open-label clinical trial.

INTRODUCTION: Malaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective; the most used being artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Pyronaridine-artesunate (PA) is a new artemisinin-based combination. The main objective of this study is to determine the efficacy and safety of PA versus AL or DP when administered to pregnant women with confirmed Plasmodium falciparum infection in the second or third trimester. The primary hypothesis is the pairwise non-inferiority of PA as compared with either AL or DP. METHODS AND ANALYSIS: A phase 3, non-inferiority, randomised, open-label clinical trial to determine the safety and efficacy of AL, DP and PA in pregnant women with malaria in five sub-Saharan, malaria-endemic countries (Burkina Faso, Democratic Republic of the Congo, Mali, Mozambique and the Gambia). A total of 1875 pregnant women will be randomised to one of the treatment arms. Women will be actively monitored until Day 63 post-treatment, at delivery and 4-6 weeks after delivery, and infants' health will be checked on their first birthday. The primary endpoint is the PCR-adjusted rate of adequate clinical and parasitological response at Day 42 in the per-protocol population. ETHICS AND DISSEMINATION: This protocol has been approved by the Ethics Committee for Health Research in Burkina Faso, the National Health Ethics Committee in the Democratic Republic of Congo, the Ethics Committee of the Faculty of Medicine and Odontostomatology/Faculty of Pharmacy in Mali, the Gambia Government/MRCG Joint Ethics Committee and the National Bioethics Committee for Health in Mozambique. Written informed consent will be obtained from each individual prior to her participation in the study. The results will be published in peer-reviewed open access journals and presented at (inter)national conferences and meetings. TRIAL REGISTRATION NUMBER: PACTR202011812241529.

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

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.

How Gender Influenced the Experience of Using a mHealth Intervention in Rural Mozambique: Secondary Qualitative Analysis of Community Health Worker Survey Data.

Background: The mixed-gender community health worker (CHW) program in Mozambique is a window into the different experiences that male and female CHWs may face in their work. The objective of this study is to investigate how gender influenced the experiences of community health workers using the PIERS on the Move (POM) mHealth app in Mozambique. Methods: This is a secondary analysis by gender of health care workers involved in the Mozambique Community Level Intervention for Pre-eclampsia (CLIP) cluster randomized trial (NCT01911494). A structured survey with 10 open-ended questions was used to elicit CHW experiences using the POM app. Data collection took place in 2017 after completion of the CLIP trial. This analysis examined emergent themes to consider how experiences may have been shaped by health worker gender. Results: Of the 43 CHWs who used the POM app, there were 31 (72%) women and 12 (28%) men. Gender differences emerged in descriptions of how using POM increased their value and respect by pregnant women and community members. Fifty-eight percent of female CHWs (18/31) said that POM positively influenced their status in the community in comparison to 33% of their male counterparts (4/12). While the small sample sizes, particularly of male CHWs who used POM, preclude conclusions, these findings were supported by qualitative results. Female CHWs tended to elaborate more about community perceptions of their increased value and status as health care providers than male CHWs. Conclusion: CHWs work within existing gender norms. While gender norms are perceived to support the comfort of women to speak to another woman about their maternal and child health issues, gender norms also work against female CHWs as their professionalism may be questioned more than for their male counterparts. CHW's narratives suggested that the mHealth intervention was valued beyond the technology itself because it also added symbolic clinical value and demonstrated a tangible investment in their professional capacities, which may have been especially appreciated by the female CHWs.

Implementation of the PIERS on the Move mHealth Application From the Perspective of Community Health Workers and Nurses in Rural Mozambique.

Background:mHealth is increasingly regarded as having the potential to support service delivery by health workers in low-resource settings. PIERS on the Move (POM) is a mobile health application developed to support community health workers identification and management of women at risk of adverse outcomes from pre-eclampsia. The objective of this study was to evaluate the impact of using POM in Mozambique on community health care workers' knowledge and self-efficacy related to caring for women with pre-eclampsia, and their perception of usefulness of the tool to inform implementation. Method: An evaluation was conducted for health care workers in the Mozambique Community Level Intervention for Pre-eclampsia (CLIP) cluster randomized trial from 2014 to 2016 in Maputo and Gaza provinces (NCT01911494). A structured survey was designed using themes from the Technology Acceptance Model, which describes the likelihood of adopting the technology based on perceived usefulness and perceived ease of use. Surveys were conducted in Portuguese and translated verbatim to English for analysis. Preliminary analysis of open-ended responses was conducted to develop a coding framework for full qualitative analysis, which was completed using NVivo12 (QSR International, Melbourne, Australia). Results: Overall, 118 community health workers (44 intervention; 74 control) and 55 nurses (23 intervention; 32 control) were surveyed regarding their experiences. Many community health workers found the POM app easy to use (80%; 35/44), useful in guiding their activities (68%; 30/44) and pregnant women received their counseling more seriously because of the POM app (75%; 33/44). Almost a third CHWs reported some challenges using the POM app (30%; 13/44), including battery depletion after a full day's activity. Community health workers reported increases in knowledge about pre-eclampsia and other pregnancy complications and increases in confidence, comfort and capacity to advise women on health conditions and deliver services. Nurses recognized the increased capacity of community health workers and were more confident in their clinical and technological skills to identify women at risk of obstetric complications. Conclusions: Many of the community health workers reported that POM improved knowledge, self-efficacy and strengthened relationships with the communities they serve and local nurses. This helped to strengthen the link between community and health facility. However, findings highlight the need to consider program and systematic challenges to implementation.

Causes and circumstances of maternal death: a secondary analysis of the Community-Level Interventions for Pre-eclampsia (CLIP) trials cohort.

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation).

Feasibility of task-sharing with community health workers for the identification, emergency management and referral of women with pre-eclampsia, in Mozambique.

BACKGROUND: Maternal mortality is an important public health problem in low-income countries. Delays in reaching health facilities and insufficient health care professionals call for innovative community-level solutions. There is limited evidence on the role of community health workers in the management of pregnancy complications. This study aimed to describe the feasibility of task-sharing the initial screening and initiation of obstetric emergency care for pre-eclampsia/eclampsia from the primary healthcare providers to community health workers in Mozambique and document healthcare facility preparedness to respond to referrals. METHOD: The study took place in Maputo and Gaza Provinces in southern Mozambique and aimed to inform the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomized controlled trial. This was a mixed-methods study. The quantitative data was collected through self-administered questionnaires completed by community health workers and a health facility survey; this data was analysed using Stata v13. The qualitative data was collected through focus group discussions and in-depth interviews with various community groups, health care providers, and policymakers. All discussions were audio-recorded and transcribed verbatim prior to thematic analysis using QSR NVivo 10. Data collection was complemented by reviewing existing documents regarding maternal health and community health worker policies, guidelines, reports and manuals. RESULTS: Community health workers in Mozambique were trained to identify the basic danger signs of pregnancy; however, they have not been trained to manage obstetric emergencies. Furthermore, barriers at health facilities were identified, including lack of equipment, shortage of supervisors, and irregular drug availability. All primary and the majority of secondary-level facilities (57%) do not provide blood transfusions or have surgical capacity, and thus such cases must be referred to the tertiary-level. Although most healthcare facilities (96%) had access to an ambulance for referrals, no transport was available from the community to the healthcare facility. CONCLUSIONS: This study showed that task-sharing for screening and pre-referral management of pre-eclampsia and eclampsia were deemed feasible and acceptable at the community-level, but an effort should be in place to address challenges at the health system level.

Maternal mortality is an important public health problem in Mozambique. Delays in reaching health facilities and insufficient health care professionals call for innovative community-level solutions. We conducted a study to describe the feasibility of task-sharing the screening and initiation of management for pre-eclampsia/eclampsia from the primary healthcare providers to community health workers in Mozambique and to document healthcare facility preparedness to respond to referrals. The study was done to inform a future intervention trial known as the Community-Level Interventions for Pre-eclampsia (CLIP) study. We interviewed community health workers, women, various community groups, health care providers, and policymakers and assessed health facilities in Maputo and Gaza provinces, Mozambique. Our results showed that community health workers in Mozambique were trained to identify the basic danger signs of pregnancy; however, they were not trained or equipped to provide obstetric emergencies care prior to referral. Nurses at primary health facilities were supportive of task-sharing with community health workers; however, some barriers mentioned include a lack of equipment, shortage of supervisors, and irregular drug availability. Local stakeholders emphasized the need for comprehensive training and supervision of community health workers to take on new tasks. Task-sharing for screening and pre-referral management of pre-eclampsia and eclampsia was deemed feasible at the community level in southern Mozambique, but still, to be addressed some health system level barriers to the management of pregnancies complications.

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.

Implementation of a Community Transport Strategy to Reduce Delays in Seeking Obstetric Care in Rural Mozambique.

INTRODUCTION: Delays due to long distances to health facilities, poor road infrastructure, and lack of affordable transport options contribute to the burden of maternal deaths in Mozambique. This study aimed to assess the implementation and uptake of an innovative community-based transport program to improve access to emergency obstetric care in southern Mozambique. METHODS: From April 2016 to February 2017, a community transport strategy was implemented as part of the Community Level Interventions for Pre-eclampsia Trial. The study aimed to reduce maternal and perinatal mortality and morbidity by 20% in intervention clusters in Maputo and Gaza Provinces, Mozambique, by involving community health workers in the identification and referral of pregnant and puerperal women at risk. Based on a community-based participatory needs assessment, the transport program was implemented with the trial. Demographics, conditions requiring transportation, means of transport used, route, and outcomes were collected during implementation. Data were entered into a REDCap database. RESULTS: Fifty-seven neighborhoods contributed to the needs assessment; of those, 13 (23%) implemented the transport program. Neighborhoods were selected based on their expression of interest and ability to contribute financially to the program (US$0.33 per family per month). In each selected neighborhood, a community management committee was created, training in small-scale financial management was conducted, and monitoring tools were provided. Twenty people from 9 neighborhoods benefited from the transport program, 70% were pregnant and postpartum women. CONCLUSION: These results demonstrate that it was feasible to implement a community-based transport program with no external input of vehicles, fuel, personnel, and maintenance. However, high cost and a lack of acceptable transport options in some communities continue to impede access to obstetric health care services and the ability for timely follow-up. When strengthening capacities of community health workers to promptly assist and refer emergency cases, it is crucial to encourage local transport programs and transportation infrastructure among minimally resourced communities to support access and engagement with health systems.

Pregnancy Outcomes and Blood Pressure Visit-to-Visit Variability and Level in Three Less-Developed Countries.

[Figure: see text].

Reduced Placental Transfer of Antibodies Against a Wide Range of Microbial and Vaccine Antigens in HIV-Infected Women in Mozambique.

Transplacental transfer of antibodies is essential for conferring protection in newborns against infectious diseases. We assessed the impact of different factors, including gestational age and maternal infections such as HIV and malaria, on the efficiency of cord blood levels and placental transfer of IgG subclasses. We measured total IgG and IgG subclasses by quantitative suspension array technology against 14 pathogens and vaccine antigens, including targets of maternal immunization, in 341 delivering HIV-uninfected and HIV-infected mother-infant pairs from southern Mozambique. We analyzed the association of maternal HIV infection, Plasmodium falciparum exposure, maternal variables and pregnancy outcomes on cord antibody levels and transplacental transfer. Our results show that maternal antibody levels were the main determinant of cord antibody levels. Univariable and multivariable analysis showed that HIV reduced the placental transfer and cord levels of IgG and IgG1 principally, but also IgG2 to half of the antigens tested. P. falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer, but this was antigen-subclass dependent. Our findings suggest that lower maternally transferred antibodies may underlie increased susceptibility to infections of HIV-exposed infants. This could affect efficacy of maternal vaccination, especially in sub-Saharan Africa, where there is a high prevalence of HIV, malaria and unfavorable environmental factors.

HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women.

OBJECTIVES: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses. METHODS: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer. RESULTS: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2. CONCLUSIONS: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children.

Population-level data on antenatal screening for proteinuria; India, Mozambique, Nigeria, Pakistan.

OBJECTIVE: To estimate the prevalence and prognosis of proteinuria at enrolment in the 27 intervention clusters of the Community-Level Interventions for Pre-eclampsia cluster randomized trials. METHODS: We identified pregnant women eligible for inclusion in the trials in their communities in four countries (2013-2017). We included women who delivered by trial end and received an intervention antenatal care visit. The intervention was a community health worker providing supplementary hypertension-oriented care, including proteinuria assessment by visual assessment of urinary dipstick at the first visit and all subsequent visits when hypertension was detected. In a multilevel regression model, we compared baseline prevalence of proteinuria (≥ 1+ or ≥ 2+) across countries. We compared the incidence of subsequent complications by baseline proteinuria. FINDINGS: Baseline proteinuria was detected in less than 5% of eligible pregnancies in each country (India: 234/6120; Mozambique: 94/4234; Nigeria: 286/7004; Pakistan: 315/10 885), almost always with normotension (India: 225/234; Mozambique: 93/94; Nigeria: 241/286; Pakistan: 264/315). There was no consistent relationship between baseline proteinuria (either ≥ 1+ or ≥ 2+) and progression to hypertension, maternal mortality or morbidity, birth at < 37 weeks, caesarean section delivery or perinatal mortality or morbidity. If proteinuria testing were restricted to women with hypertension, we projected annual cost savings of 153 223 981 United States dollars (US$) in India, US$ 9 055 286 in Mozambique, US$ 53 181 933 in Nigeria and US$ 38 828 746 in Pakistan. CONCLUSION: Our findings question the recommendations to routinely evaluate proteinuria at first assessment in pregnancy. Restricting proteinuria testing to pregnant women with hypertension has the potential to save resources.

Association of Maternal Factors and HIV Infection With Innate Cytokine Responses of Delivering Mothers and Newborns in Mozambique.

Maternal factors and exposure to pathogens have an impact on infant health. For instance, HIV exposed but uninfected infants have higher morbidity and mortality than HIV unexposed infants. Innate responses are the first line of defense and orchestrate the subsequent adaptive immune response and are especially relevant in newborns. To determine the association of maternal HIV infection with maternal and newborn innate immunity we analyzed the cytokine responses upon pattern recognition receptor (PRR) stimulations in the triad of maternal peripheral and placental blood as well as in cord blood in a cohort of mother-infant pairs from southern Mozambique. A total of 48 women (35 HIV-uninfected and 13 HIV-infected) were included. Women and infant innate responses positively correlated with each other. Age, gravidity and sex of the fetus had some associations with spontaneous production of cytokines in the maternal peripheral blood. HIV-infected women not receiving antiretroviral therapy (ART) before pregnancy showed decreased IL-8 and IL-6 PRR responses in peripheral blood compared to those HIV-uninfected, and PRR hyporesponsiveness for IL-8 was also found in the corresponding infant's cord blood. HIV infection had a greater impact on placental blood responses, with significantly increased pro-inflammatory, T H 1 and T H 17 PRR responses in HIV-infected women not receiving ART before pregnancy compared to HIV-uninfected women. In conclusion, innate response of the mother and her newborn was altered by HIV infection in the women who did not receive ART before pregnancy. As these responses could be related to birth outcomes, targeted innate immune modulation could improve maternal and newborn health.

Community-level interventions for pre-eclampsia (CLIP) in Mozambique: A cluster randomised controlled trial

Objectives: Pregnancy hypertension is the third leading cause of maternal mortality in Mozambique and contributes significantly to fetal and neonatal mortality. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment. Study design: The Mozambique Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 administrative posts (clusters) in Maputo and Gaza Provinces. The CLIP intervention (6 clusters) consisted of community engagement, community health worker-provided mobile health-guided clinical assessment, initial treatment, and referral to facility either urgently (<4hrs) or non-urgently (<24hrs), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of CLIP contacts. Main outcome measures: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity. Results: 15,013 women (15,123 pregnancies) were recruited in intervention (N = 7930; 2·0% loss to follow-up (LTFU)) and control (N = 7190; 2·8% LTFU) clusters. The primary outcome did not differ between intervention and control clusters (adjusted odds ratio (aOR) 1·31, 95% confidence interval (CI) [0·70, 2·48]; p = 0·40). Compared with intervention arm women without CLIP contacts, those with ≥8 contacts experienced fewer primary outcomes (aOR 0·79 (95% CI 0·63, 0·99); p = 0·041), primarily due to improved maternal outcomes (aOR 0·72 (95% CI 0·53, 0·97); p = 0·033). Interpretation: As generally implemented, the CLIP intervention did not improve pregnancy outcomes; community implementation of the WHO eight contact model may be beneficial. Funding: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).

Community-level interventions for pre-eclampsia (CLIP) in Mozambique: A cluster randomised controlled trial.

OBJECTIVES: Pregnancy hypertension is the third leading cause of maternal mortality in Mozambique and contributes significantly to fetal and neonatal mortality. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment. STUDY DESIGN: The Mozambique Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 administrative posts (clusters) in Maputo and Gaza Provinces. The CLIP intervention (6 clusters) consisted of community engagement, community health worker-provided mobile health-guided clinical assessment, initial treatment, and referral to facility either urgently (<4hrs) or non-urgently (<24hrs), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of CLIP contacts. MAIN OUTCOME MEASURES: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity. RESULTS: 15,013 women (15,123 pregnancies) were recruited in intervention (N = 7930; 2·0% loss to follow-up (LTFU)) and control (N = 7190; 2·8% LTFU) clusters. The primary outcome did not differ between intervention and control clusters (adjusted odds ratio (aOR) 1·31, 95% confidence interval (CI) [0·70, 2·48]; p = 0·40). Compared with intervention arm women without CLIP contacts, those with ≥8 contacts experienced fewer primary outcomes (aOR 0·79 (95% CI 0·63, 0·99); p = 0·041), primarily due to improved maternal outcomes (aOR 0·72 (95% CI 0·53, 0·97); p = 0·033). INTERPRETATION: As generally implemented, the CLIP intervention did not improve pregnancy outcomes; community implementation of the WHO eight contact model may be beneficial. FUNDING: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).

First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age.

BACKGROUND: While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth. METHODS: Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site). RESULTS: Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high. CONCLUSION: ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

Obstetric fistula in southern Mozambique: a qualitative study on women's experiences of care pregnancy, delivery and post-partum.

BACKGROUND: Obstetric fistula is still common in low- and middle-income countries (LMIC) despite the on-going shift to increased facility deliveries in the same settings. The social behavioural circumstances in which fistula, as well as its consequences, still occur are poorly documented, particularly from the perspective of the experiences of women with obstetric fistula. This study sought to describe women's experiences of antenatal, partum and post-partum care in southern Mozambique, and to pinpoint those experiences that are unique to women with fistula in order to understand the care-seeking and care provision circumstances which could have been modified to avoid or mitigate the onset or consequences of fistula. METHODS: This study took place in Maputo and Gaza provinces, southern Mozambique, in 2016-2017. Qualitative data were collected through in-depth interviews conducted with 14 women with positive diagnoses of fistula and an equal number of women without fistula. All interviews were audio-recorded and transcribed verbatim prior to thematic analysis using NVivo11. RESULTS: Study participants had all attended antenatal care (ANC) visits and had prepared for a facility birth. Prolonged or obstructed labour, multiple referrals, and delays in receiving secondary and tertiary health care were common among the discourses of women with fistula. The term "fistula" was rarely known among participants, but the condition (referred to as "loss of water" or "illness of spillage") was recognised after being prompted on its signs and symptoms. Women with fistula were invariably aware of the links between fistula and poor birth assistance, in contrast with those without fistula, who blamed the condition on women's physiological and behavioural characteristics. CONCLUSION: Although women do seek antenatal and peri-partum care in health facilities, deficiencies and delays in birth assistance, referral and life-saving interventions were commonly reported by women with fistula. Furthermore, weaknesses in quality of care, not only in relation to prevention, but also the resolution of the damage, were evident. Quality improvement of birth care is necessary, both at primary and referral level. There is a need to increase awareness and develop guidelines for prevention, early detection and management of obstetric fistula, including early postpartum treatment, availability of fistula repair for complex cases, and rehabilitation, coupled with the promotion of community consciousness of the problem.

VAR2CSA Serology to Detect Plasmodium falciparum Transmission Patterns in Pregnancy.

Pregnant women constitute a promising sentinel group for continuous monitoring of malaria transmission. To identify antibody signatures of recent Plasmodium falciparum exposure during pregnancy, we dissected IgG responses against VAR2CSA, the parasite antigen that mediates placental sequestration. We used a multiplex peptide-based suspension array in 2,354 samples from pregnant women from Mozambique, Benin, Kenya, Gabon, Tanzania, and Spain. Two VAR2CSA peptides of limited polymorphism were immunogenic and targeted by IgG responses readily boosted during infection and with estimated half-lives of <2 years. Seroprevalence against these peptides reflected declines and rebounds of transmission in southern Mozambique during 2004-2012, reduced exposure associated with use of preventive measures during pregnancy, and local clusters of transmission that were missed by detection of P. falciparum infections. These data suggest that VAR2CSA serology can provide a useful adjunct for the fine-scale estimation of the malaria burden among pregnant women over time and space.