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Abstract Background Eotaxin-1 concentrations in plasma have been inversely associated with malaria exposure, malaria infection and pregnancy, but the effect of these conditions on the levels of the related chemokines eotaxin-2 and eotaxin-3 remains unknown. Methods Eotaxin-2 and -3 concentrations were measured in 310 peripheral or placental plasma samples from pregnant and non-pregnant individuals from Papua New Guinea (malaria-endemic country) and Spain (malaria-naïve individuals) with previous data on eotaxin-1 concentrations. Correlations between eotaxin concentrations were examined with the Spearman’s test. Differences in eotaxin concentrations among groups were evaluated with the Kruskal–Wallis or Mann Whitney tests. The pairwise Wilcoxon test was performed to compare eotaxin-2 concentration between peripheral and placental matched plasmas. Univariable and multivariable linear regression models were estimated to assess the association between eotaxins and Plasmodium infection or gestational age. Results Eotaxin-2 concentrations in plasma showed a weak positive correlation with eotaxin-3 (rho = 0.35, p

Abstract Background European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)–piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Methods Participants were recruited through Health Care Provider’s safety registry in 15 centres across 6 European countries in the period 2013–2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett’s (QTcB) or Fridericia’s (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Results Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). Conclusions APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942

Background The epidemic of Zika virus (ZIKV) was associated with a sudden and unprecedented increase in infants born with microcephaly. Colombia was the second most affected country by the epidemic in the Americas. Primary caregivers of children with ZIKV-associated microcephaly, their mothers mainly, were at higher risk of suffering anxiety and depression. Often, these women were stigmatized and abandoned by their partners, relatives, and communities. Methodology/Principal findings This study aimed to understand the perceptions about ZIKV infection among mothers of children born with microcephaly during the ZIKV epidemic in Caribbean Colombia, and the barriers and facilitators affecting child health follow-up. An exploratory qualitative study, based on Phenomenology and Grounded Theory, was conducted in Caribbean Colombia. Data were collected through In-Depth Interviews (IDI) from women who delivered a baby with microcephaly during the ZIKV epidemic at Clínica Salud Social, Sincelejo, Sucre District (N = 11). The themes that emerged during the interviews included experiences from their lives before pregnancy; knowledge about ZIKV; experiences and perceptions when diagnosed; considering a possible termination of pregnancy, and children’s clinical follow-up. In some cases, women reported having been told they were having a baby with microcephaly but decided not to terminate the pregnancy; while in other cases, women found out about their newborn’s microcephaly condition only at birth. The main barriers encountered by participants during children’s follow-up included the lack of psychosocial and economic support, the stigmatization and abandonment by some partners and relatives, and the frustration of seeing the impaired development of their children. Conclusions This study contributed to identifying the social, medical, psychological, and economic needs of families with children affected by the ZIKV epidemic. Commitment and action by local and national governments, and international bodies, is required to ensure sustained and quality health services by affected children and their families. Author summary As of January 2018, nearly 4000 cases of children with congenital birth defects associated with Zika virus infection, included microcephaly, had been reported in the Americas. In 2019, we interviewed eleven mothers of children with microcephaly in Colombia, a country heavily affected by the Zika epidemic. Most women were young, lived in peri-urban areas were of low socioeconomic status, according to official government classification in Colombia. They reported knowing that the virus was transmitted by mosquitoes, and how to prevent mosquito bites, yet they were not aware of Zika infection being transmitted by sexual contact. Most women had been tested for Zika during pregnancy but did not receive their laboratory results. Also, they complained that they had not received enough information from healthcare providers. When fetal anomalies were detected prenatally, only a few of them were offered the possibility to terminate the pregnancy. Women reported a lack of both economic and psychosocial support to deal with the special health care needs their children required. The results of this study highlight the struggles and challenges of families of children severely affected by the Zika virus and provide valuable information for health policy making as part of the next epidemic preparedness and response.

Resumo em Português Antecedentes Moçambique tem uma das maiores taxas de incidência de cancro do colo do útero no mundo. As intervenções de saúde para o cancro do colo do útero ainda têm sido concebidas apenas do ponto de vista de doenças não transmissíveis, apesar do cancro do colo do útero ser também uma problema de saúde sexual e reprodutiva. O objectivo do estudo foi de avaliar em que medida as percepções leigas sobre o cancro do colo do útero alinham-se com o conhecimento biomédico do ponto de vista de saúde sexual e reprodutiva. Métodos Foram realizadas 10 discussões em grupos focais com 10 grupos-alvo no distrito de Manhiça. Os grupos-alvo eram diversos em termos de idade, sexo, nível de educação e ocupação. O estudo envolveu um total 116 participantes. As discussões em grupos focais geraram informação verbal e desencadearam debates sobre crenças e atitudes em relação ao cancro do colo do útero, e também exploraram noções de transmissão e etiologia da doença. As discussões foram gravadas para posterior transcrição e análise, seguindo uma combinação de análise de conteúdo e temática. Resultados Os participantes estavam familiarizados com o termo biomédico “cancro do colo do útero “, mas o seu conhecimento sobre a sua etiologia e transmissão era limitado. O cancro do colo do útero foi associado à transmissão sexual e infecções sexualmente transmissíveis e concebido como uma “ferida que não cicatriza”. O termo “cancro” causou confusão, pois era percebido como ocorrendo apenas nos membros do corpo, entendido como hereditário, não transmissível e como uma doença do Ocidente. Conclusão As percepções leigas sobre o cancro do colo do útero alinham-se, em grande parte às definições biomédicas, portanto, há uma estrutura de base comum para enquadrar futuras intervenções de saúde do ponto de vista da saúde sexual e reprodutiva.

The World Health Organization (WHO) identified vaccine hesitancy as one of the top 10 threats to global health in 2019. Health promotion and education have been seen to improve knowledge and uptake of vaccinations in pregnancy. This qualitative study was conducted based on phenomenology, a methodological approach to understand first-hand experiences, and grounded theory, an inductive approach to analyse data, where theoretical generalisations emerge. Data were collected through semi-structured interviews with pregnant women attending antenatal care services and healthcare workers (HCWs) in Barcelona, Spain. Interviews were audio-recorded, transcribed, and coded, and notes were taken. Inductive thematic analysis was performed, and data were manually coded. Pertussis was reported as the most trusted vaccine among pregnant women due to its long-standing background as a recommended vaccine in pregnancy. The influenza vaccine was regarded as less important since it was perceived to cause mild disease. The COVID-19 vaccine was the least trustworthy for pregnant women due to uncertainties about effectiveness, health effects in the mid- and long-term, the fast development of the vaccine mRNA technology, and the perceptions of limited data on vaccine safety. However, the necessity to be vaccinated was justified by pregnant women due to the exceptional circumstances of the COVID-19 pandemic. The recommendations provided by HCW and the established relationship between the HCW, particularly midwives, and pregnant women were the main factors affecting decision-making. The role of mass media was perceived as key to helping provide reliable messages about the need for vaccines during pregnancy. Overall, vaccines administered during pregnancy were perceived as great tools associated with better health and improved quality of life. Pregnancy was envisioned as a vulnerable period in women’s lives that required risk–benefits assessments for decision-making about maternal vaccinations. A holistic approach involving the community and society was considered crucial for health education regarding maternal vaccines in support of the work conducted by HCWs.

COVID-19 is associated with poor maternal and pregnancy outcomes. COVID-19 vaccination is recommended in Spain, yet vaccination rates in pregnancy are suboptimal. This study investigates the perceptions of pregnant women and healthcare workers (HCW) regarding COVID-19 vaccination. A web-based cross-sectional quantitative study was conducted in 2021–2022 among 302 pregnant women and 309 HCWs in the Catalan public health system. Most pregnant women (83%) and HCWs (86%) were aware of COVID-19 maternal vaccines. The recommendation of the COVID-19 vaccination by an HCW was identified as the greatest facilitator for maternal vaccine uptake, while the fear of harming the foetus was the most significant barrier reported for rejecting vaccination. HCWs recognised they received limited information and training about COVID-19 vaccination in pregnancy, which hindered them from providing informed recommendations. This study highlights that information and education on COVID-19 vaccines to pregnant women and health professionals are pivotal to ensuring informed decision-making and increasing vaccine uptake.

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa. The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization.

Abstract Objectives The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. Trial design Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. Participants Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. • Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact* of a SARS-CoV-2 confirmed or suspected case in the past 14 days • More than 12 weeks of gestation (dated by ultrasonography) • Agreement to deliver in the study hospitals Exclusion criteria • Known hypersensitivity to HCQ or other 4-amonoquinoline compounds • History of retinopathy of any aetiology • Concomitant use of digoxin, cyclosporine, cimetidine • Known liver disease • Clinical history of cardiac pathology including known long QT syndrome • Unable to cooperate with the requirements of the study • Participating in other intervention studies • Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: • SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) • SARS-CoV-2 PCR negative pregnant women in contact* with a SARS-CoV-2-infected confirmed or suspected case (n=514). *The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. Intervention and comparator Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). Main outcomes The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). Randomisation Allocation of participants to study arms will be done centrally by the trial’s Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. Blinding (masking) Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. Numbers to be randomised (sample size) This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. Trial Status Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). Trial registration EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562 , retrospectively registered 1 June 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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

Background Social accountability or citizen-led accountability has been promoted in many low- and middle-income countries to improve the quality, access to and use of maternal health services. Experiences with social accountability in maternal health services in Nepal have not yet been documented. This study identifies existing social accountability structures and activities in maternal health services in two districts of Far-Western Nepal and explores their functions, implementation and gaps/challenges. Methods An exploratory study was conducted that included in-depth interviews with purposively selected policy advisors (8), healthcare officials (11), healthcare providers (12) and non-governmental staff (3); and focus group discussions (FGDs) with 54 women. Data analysis was conducted using thematic content analysis based on George’s information, dialogue and negotiation framework. Results Social accountability in maternal health existed in terms of structures such as mothers’ groups (MGs), female community health volunteers (FCHVs) and Health Facility Operation and Management Committees (HFOMCs); and activities such as social audits and community health score board (CHSB). MGs and FCHVs were perceived as trusted intermediaries, but their functioning was limited to information. HFOMCs were not fully functional. Social audits and CHSBs were implemented in limited sites and with poor participation by women. Health-sector responses were mainly found at the local level. Factors contributing to these challenges were the absence of a mandate and limited capacity, including resources. Conclusion Formal structures and activities existed for social accountability in maternal health services in the Far-Western Development Region of Nepal, but there were limitations pertaining to their implementation. The main recommendations are: for clear policy mandates on the social accountability roles of MGs and FCHVs; wider implementation of social audits and CHSBs, with emphasis on the participation of women from disadvantaged groups; improved capacity of HFOMCs; and improved engagement of the health sector at all levels to listen and respond to women’s concerns.

Plasmodium vivax malaria is a neglected disease, particularly during pregnancy. Severe vivax malaria is associated with inflammatory responses but in pregnancy immune alterations make it uncertain as to what cytokine signatures predominate, and how the type and quantity of blood immune mediators influence delivery outcomes. We measured the plasma concentrations of a set of thirty-one biomarkers, comprising cytokines, chemokines and growth factors, in 987 plasma samples from a cohort of 572 pregnant women from five malaria-endemic tropical countries and related these concentrations to delivery outcomes (birth weight and hemoglobin levels) and malaria infection. Samples were collected at recruitment (first antenatal visit) and at delivery (periphery, cord and placenta). At recruitment, we found that P. vivax-infected pregnant women had higher plasma concentrations of proinflammatory (IL-6, IL-1β, CCL4, CCL2, CXCL10) and TH1-related cytokines (mainly IL-12) than uninfected women. This biomarker signature was essentially lost at delivery and was not associated with birth weight nor hemoglobin levels. Antiinflammatory cytokines (IL-10) were positively associated with infection and poor delivery outcomes. CCL11 was the only biomarker to show a negative association with P. vivax infection and its concentration at recruitment was positively associated with hemoglobin levels at delivery. Birth weight was negatively associated with peripheral IL-4 levels at delivery. Our multi-biomarker multicenter study is the first comprehensive one to characterize the immunological signature of P. vivax infection in pregnancy thus far. In conclusion, data show that while TH1 and pro-inflammatory responses are dominant during P. vivax infection in pregnancy, antiinflammatory cytokines may compensate excessive inflammation avoiding poor delivery outcomes, and skewness toward a TH2 response may trigger worse delivery outcomes. CCL11, a chemokine largely neglected in the field of malaria, emerges as an important marker of exposure or mediator in this condition.

Summary: Background: About 3·7 billion doses of ivermectin have been distributed in mass drug administration (MDA) campaigns globally over the past 30 years. At 10–100 times higher than current human doses, ivermectin is a known teratogen in mammals. During these campaigns with recommended doses, pregnant women might be inadvertently exposed. We therefore aimed to evaluate the existing evidence for serious and non-serious adverse events after ivermectin exposure in pregnant women. Methods: For this systematic review and meta-analysis, we searched relevant databases and trial registry platforms on July 15, 2018, for randomised controlled trials (RCTs) and observational studies that reported adverse events in pregnant women. We did not use language or date restrictions. Outcomes of interest were spontaneous abortions, stillbirths, congenital anomalies, and neonatal death (serious adverse events), as well as maternal morbidity, preterm births, and low birthweight (adverse events). The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for RCTs. We did the meta-analysis of observational studies and RCTs separately. The quality of evidence was assessed using the GRADE approach. The study protocol is registered with PROSPERO, protocol CRD42016046914. Findings: We identified 147 records, of which only five observational studies and one RCT were included for quantitative analysis; these studies were published between 1990 and 2008, and were done in six African countries. 893 women with 899 pregancy outcomes were included, of whom 496 pregnant women (500 pregnancy outcomes) received ivermectin inadvertently during MDA campaigns in the observational studies and 397 pregnant women (399 pregnancy outcomes) purposely received ivermectin as part of the open-label RCT. No study reported neonatal deaths, maternal morbidity, preterm births, or low birthweight. It is unclear whether exposure to ivermectin during pregnancy increases the risk of spontaneous abortions and stillbirths (odds ratio [OR] 1·15 [95% CI 0·75–1·78] with very low certainty of evidence for the four observational studies and 0·62 [0·18–2·14] with very low certainty of evidence for the RCT) or congenital anomalies (OR 1·69 [95% CI 0·83–3·41] with very low certainty of evidence for the five observational studies and 1·10 [0·07–17·65] with very low certainty of evidence for the RCT). Interpretation: There is insufficient evidence to conclude on the safety profile of ivermectin during pregnancy. Treatment campaigns should focus additional efforts on preventing inadvertent treatment of pregnant women. Funding: Unitaid.

Abstract Background Disruption of malaria control strategies during the West African 2014–2016 Ebola epidemic led to an increase in malaria-attributable mortality. However, recent data on malaria infection in vulnerable groups, such as pregnant women, are lacking in this post-Ebola scenario. This cross-sectional study aimed to assess the prevalence of Plasmodium falciparum infection and of molecular markers of drug resistance among pregnant women attending antenatal care in Monrovia, capital of Liberia. Methods From October 2016 to June 2017, all pregnant women attending their first antenatal care visit at the Saint Joseph’s Catholic Hospital, Monrovia, were invited to participate in the study. In addition to their routine antenatal care tests, capillary blood spotted onto filter papers were collected from all consenting participants to determine presence of P. falciparum by real-time quantitative PCR. Molecular markers of anti-malarial drug resistance were assessed through Sanger sequencing and quantitative PCR in specimens positive for P. falciparum analysis. Results Of the 195 women participants, 24 (12.3%) were P. falciparum-positive by qPCR. Infected women tended to be more commonly primigravidae and younger than uninfected ones. Parasite densities were higher in primigravidae. Fever was more frequently detected among the infected women. No statistically significant association between P. falciparum infection and haemoglobin levels or insecticide-treated net use was found. While high prevalence of genetic polymorphisms associated with chloroquine and amodiaquine resistance were detected, no molecular markers of artemisinin resistance were observed. Conclusion Plasmodium falciparum infections are expected to occur in at least one in every eight women attending first ANC at private clinics in Monrovia and outside the peak of the rainy season. Young primigravidae are at increased risk of P. falciparum infection. Molecular analyses did not provide evidence of resistance to artemisinins among the P. falciparum isolates tested. Further epidemiological studies involving pregnant women are necessary to describe the risk of malaria in this highly susceptible group outside Monrovia, as well as to closely monitor the emergence of resistance to anti-malarials, as recommended by the Liberian National Malaria Control Programme.

Abstract Background Social accountability mechanisms have been highlighted as making a contribution to improving maternal health outcomes and reducing inequities. But there is a lack of evidence on how they contribute to such improvements. This study aims to explore social accountability mechanisms in selected districts of the Indian state of Gujarat in relation to maternal health, the factors they address and how the results of these mechanisms are perceived. Methods We conducted qualitative research through in-depth interviews and focus group discussions with actors of civil society and government health system. Data were analyzed using a framework of social determinants of maternal health in terms of structural and intermediary determinants. Results There are social accountability mechanisms in the government and civil society in terms of structure and activities. But those that were perceived to influence maternal health were mainly from civil society, particularly women’s groups, community monitoring and a maternal death review. The social accountability mechanisms influenced structural determinants – governance, policy, health beliefs, women’s status, and intermediary determinants – social capital, maternal healthcare behavior, and availability, accessibility and the quality of the health service delivery system. These further positively influenced the increased use of maternal health services. The social accountability mechanisms, through the process of information, dialogue and negotiation, particularly empowered women to make collective demands of the health system and brought about changed perceptions of women among actors in the system. It ultimately improved relations between women and the health system in terms of trust and collaboration, and generated appropriate responses from the health system to meeting women’s groups’ demands. Conclusion Social accountability mechanisms in Gujarat were perceived to improve interaction between communities and the health system and contribute to improvements in access to and use of maternal health services. The influence of social accountability appeared to be limited to the local/district level and there was lack of capacity and ownership of the government structures.

Sub-Saharan Africa concentrates the largest burden of cervical cancer worldwide. The introduction of the HPV vaccination in this region is urgent and strategic to meet global health targets. This was a cross-sectional study conducted in Mozambique prior to the first round of the HPV vaccine demonstration programme. It targeted girls aged 10–19 years old identified from schools and households. Face-to-face structured interviews were conducted. A total of 1147 adolescents were enrolled in three selected districts of the country. Most girls [84% (967/1147)] had heard of cervical cancer, while 76% believed that cervical cancer could be prevented. However only 33% (373/1144) of girls recognized having ever heard of HPV. When girls were asked whether they would accept to be vaccinated if a vaccine was available in Mozambique, 91% (1025/1130) answered positively. Girls from the HPV demonstration districts showed higher awareness on HPV and cervical cancer, and willingness to be vaccinated. This study anticipates high acceptability of the HPV vaccine in Mozambique and high awareness about cervical cancer, despite low HPV knowledge. These results highlight that targeted health education programmes are critical for acceptance of new tools, and are encouraging for the reduction of cervical cancer related mortality and morbidity in Mozambique. Keywords: Human papillomavirus, Vaccine, Cervical cancer, Mozambique, Awareness and acceptability

Abstract Background Quality antenatal care (ANC) is recognised as an opportunity for screening and early identification of pregnancy-related complications. In rural Ghana, challenges with access to diagnostic services demotivate women from ANC attendance and referral compliance, leading to absent or late identification and management of high-risk women. In 2016, an integrated diagnostic and clinical decision support system tagged ‘Bliss4Midwives’ (B4M), was piloted in Northern Ghana. The device facilitated non-invasive screening of pre-eclampsia, gestational diabetes and anaemia at the point-of-care. This study aimed to explore the experiences of pregnant women with B4M, and its influence on service utilisation (“pull effect”) and woman-provider relationships (“woman engagement”). Methods Through an embedded study design, qualitative methods including individual semi-structured interviews and non-participant observation were employed. Interviews were conducted with 20 pregnant women and 10 health workers, supplemented by ANC observations in intervention facilities. Secondary data on ANC registrations over a one-year period were extracted from health facility records to support findings on the perceived influence of B4M on service utilisation. Results Women’s first impressions of the device were mostly emotive (excitement, fear), but sometimes neutral. Although it is inconclusive whether B4M increased ANC registration, pregnant women generally valued the availability of diagnostic services at the point-of-care. Additionally, by fostering some level of engagement, the intervention made women feel listened to and cared for. Process outcomes of the B4M encounter also showed that it was perceived as improving the skills and knowledge of the health worker, which facilitated trust in diagnostic recommendations and was therefore believed to motivate referral compliance. Conclusions This study suggests that mHealth diagnostic and decision support devices enhance woman engagement and trust in health workers skills. There is need for further inquiry into how these interventions influence maternal health service utilization and women’s expectations of pregnancy care.

We report a case of spontaneous abortion associated with Zika virus infection in a pregnant woman who traveled from Spain to the Dominican Republic and developed a rash. Maternal Zika viremia persisted at least 31 days after onset of symptoms and 21 days after uterine evacuation.

BackgroundNepal has one of the highest rates of maternal mortality in the South Asia region, partly due to the underutilization of maternal health services and the high number of adolescent pregnancies. This study explores married Nepali adolescent girls' healthcare-seeking behaviour throughout their pregnancies, during their delivery and postpartum.MethodsWe conducted a prospective qualitative study in Banke district, Nepal. In-depth interviews were conducted with 27 married adolescent girls before and after delivery. In addition, a focus group discussion was conducted with community health works and key-informant interviews were conducted with family members of adolescent girls, representatives from the government and health care providers. We applied the Social-Ecological Model (SEM) as a framework to guide thematic content analysis and presentation of our qualitative data.ResultsSeveral factors in the SEM influenced maternal health care-seeking behaviour of adolescents. At the individual level, girls' perceptions, their lack of knowledge about maternal and reproductive health, certain traditional practices, their sole dependency on their husbands and mothers-in-laws and their low decision-making autonomy towards their own health care negatively influenced their utilization of skilled maternal health services. Mothers-in-law and other family members played a critical role in either encouraging or discouraging the use of skilled maternal health services. At the health systems level, lack of adolescent-friendly maternal health services, difficulties in accessing quality maternal health services, and the fixed operating hours of public health facilities restricted their ability to obtain services. The existence of the Safe Motherhood Programme, knowledge sharing platforms such as "women's groups" and the active role of Female Community Health Volunteers (FCHVs) positively influenced utilization of skilled maternal health services among these girls.ConclusionInfluences on married adolescent girls' use of skilled maternal health services in Banke District, Nepal were multi-factoral. Ensuring easy access and availability of adolescent-friendly maternal health services are important to encourage adolescent girls to use skilled maternal health services. Moreover, interventions are needed to improve adolescent girls' knowledge of maternal health, keep them in school, involve family members (mainly mothers-in-law) in health interventions, as well as overcome negative traditional beliefs within the community that discourage care-seeking for skilled maternal health services.

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 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.

Mosquito-borne viruses such as dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV) have spread in recent decades. We aimed to assess seroprevalence of arboviral infections in pregnant women living in Cereté, Caribbean Colombia. In 2016 a cross-sectional facility-based sero-survey study was performed among pregnant women (N = 90). Most of them (66%) reported at least one symptom or sign compatible with arboviral infection over the previous 15 days. All screened women had a positive IgG for DENV, 89% for ZIKV, and 82% for CHIKV. One woman tested positive for ZIKV IgM. This study shows the high exposure among pregnant women to arboviruses in endemic areas, shown by the high seroprevalence of past arboviral infections. Given the evidence on the potential risks of these arboviral infections on pregnancy and infant outcomes, these results highlight the need for continuous epidemiological surveillance of arboviral diseases, particularly among those most of risk of their harmful consequences.

Zika virus (ZIKV) can cause pregnancy loss and congenital Zika syndrome, among other poor health outcomes. The ZIKV epidemic in 2015–2017 disproportionately affected pregnant women in poor-resource settings. We aimed to understand perceptions and attitudes towards a hypothetical ZIKV vaccine, women’s willingness to be vaccinated, and potential barriers and facilitators for vaccine acceptance in 1) migrant women living in Spain who travelled to their countries of origin and were diagnosed with ZIKV infection during pregnancy, and their healthcare providers, and 2) women living in Colombia who delivered a child with microcephaly. An exploratory qualitative study based on phenomenology and grounded theory was conducted. Data were collected through in-depth, paired and semi-structured interviews. Overall, women from both sites were willing to receive a hypothetical ZIKV vaccine. However, some expressed concerns of being vaccinated during pregnancy, yet they would accept it if the vaccine was recommended by a healthcare professional they trust. Main fears towards vaccination were related to vaccine safety and potential adverse effects on child’s health. Women reported feeling hesitant to participate in a ZIKV vaccine trial. These results may contribute to guiding the effective delivery of future ZIKV vaccines among populations most at risk and particularly vulnerable.

# Background Despite there being many state and non-governmental organisation (NGO) health programs, Nepal still has a high maternal mortality ratio of 258. Previous research has indicated that social accountability mechanisms can improve maternal health. However, the functioning of these mechanisms has not yet been explored in Nepal. Social accountability mechanisms can be identified and analysed through the information, dialogue & negotiation model. # Objective To identify the role of social accountability mechanisms in maternal health and the challenges regarding these mechanisms in Baglung district, Nepal. # Methods Ten semi-structured interviews were held with healthcare officials, healthcare providers, NGO staff and mothers at the community level, and four focus group discussions were held with pregnant women and recent mothers, healthcare providers and Health Facility Operation and Management Committee (HFOMC) members. Data was coded and analysed with ATLAS.ti using the information, dialogue & negotiation model. # Results Mothers' Groups, Female Community Health Volunteers (FCHVs) and the HFOMC function as a two-step social accountability mechanism. The FCHVs act as a bridge between Mothers' Groups at the community level and the HFOMC. The HFOMC holds dialogues and negotiations with the district and central government. There seem to be two main obstructions in the information flow from the central or district levels to the community. They are located between the central government level and/or district level and the HFOMC, and between the HFOMC and the FCHV and Mothers\' Groups. The information from the community to higher levels seems to have an obstruction in the voicing of service-related needs/complaints in the Mothers' Groups and another obstruction of HFOMCs rarely interacting with health sector actors other than the local health facility. # Conclusions The information, dialogue & negotiation model is a sensitive analytical model to understand the functioning and challenges of social accountability in the maternal health care system of Nepal. The community-based accountability chain of HFOMC, FCHVs and Mothers' Groups presents a structure that facilitates the optimisation of maternal health services. Recommendations are given to improve gaps in this accountability chain.

Malaria in pregnancy threatens birth outcomes and the health of women and their newborns. This is also the case in low transmission areas, such as Colombia, where Plasmodium vivax is the dominant parasite species. Within the Colombian health system, which underwent major reforms in the 90s, malaria treatment is provided free of charge to patients. However, patients still incur costs, such as transportation and value of time lost due to the disease. We estimated such costs among 40 pregnant women with clinical malaria (30% Plasmodium falciparum, 70% Plasmodium vivax) in the municipality of Tierralta, Northern Colombia. In a cross-sectional study, women were interviewed after an outpatient or inpatient laboratory confirmed malaria episode. Women were asked to report all types of cost incurred before (including prevention), during and immediately after the contact with the health facility. Median total cost was over 16US$ for an outpatient visit, rising to nearly 30US$ if other treatments were sought before reaching the health facility. Median total inpatient cost was 26US$ or 54US$ depending on whether costs incurred prior to admission were excluded or included. For both outpatients and inpatients, direct costs were largely due to transportation and indirect costs constituted the largest share of total costs. Estimated costs are likely to represent only one of the constraints that women face when seeking treatment in an area characterized, at the time of the study, by armed conflict, displacement, and high vulnerability of indigenous women, the group at highest risk of malaria. Importantly, the Colombian peace process, which culminated with the cease-fire in August 2016, may have a positive impact on achieving universal access to healthcare in conflict areas. The current study can inform malaria elimination initiatives in Colombia.

In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation.

Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy.We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG). Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery. A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery. Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR. P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%]. P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR. P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR]. Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83-16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb

The huge proportion of child marriage contributes to high rates of pregnancies among adolescent girls in Bangladesh. Despite substantial progress in reducing maternal mortality in the last two decades, the rate of adolescent pregnancy remains high. The use of skilled maternal health services is still low in Bangladesh. Several quantitative studies described the use of skilled maternal health services among adolescent girls. So far, very little qualitative evidence exists about attitudes and practices related to maternal health. To fill this gap, we aimed at exploring maternal health care-seeking behavior of adolescent girls and their experiences related to pregnancy and delivery in Bangladesh.A prospective qualitative study was conducted among thirty married adolescent girls from three Upazilas (sub-districts) of Rangpur district. They were interviewed in two subsequent phases (2014 and 2015). To triangulate and validate the data collected from these married adolescent girls, key informant interviews (KIIs) and focus group discussions (FGDs) were conducted with different stakeholders. Data analysis was guided by the Social-Ecological Model (SEM) including four levels of factors (individual, interpersonal and family, community and social, and organizational and health systems level) which influenced the maternal health care-seeking behavior of adolescent girls. While adolescent girls showed little decision making-autonomy, interpersonal and family level factors played an important role in their use of skilled maternal health services. In addition, community and social factors and as well as organizational and health systems factors shaped adolescent girls' maternal health care-seeking behavior.In order to improve the maternal health of adolescent girls, all four levels of factors of SEM should be taken into account while developing health interventions targeting adolescent girls.

Pregnant women exposed to Plasmodium falciparum generate antibodies against VAR2CSA, the parasite protein that mediates adhesion of infected erythrocytes to the placenta. There is a need of high-throughput tools to determine the fine specificity of these antibodies that can be used to identify immune correlates of protection and exposure. Here we aimed at developing a multiplex-immunoassay to detect antibodies against VAR2CSA antigens.We constructed two multiplex-bead arrays, one composed of 3 VAR2CSA recombinant-domains (DBL3X, DBL5Ɛ and DBL6Ɛ) and another composed of 46 new peptides covering VAR2CSA conserved and semi-conserved regions. IgG reactivity was similar in multiplexed and singleplexed determinations (Pearson correlation, protein array: R2 = 0.99 and peptide array: R2 = 0.87). IgG recognition of 25 out of 46 peptides and all recombinant-domains was higher in pregnant Mozambican women (n = 106) than in Mozambican men (n = 102) and Spanish individuals (n = 101; p

BACKGROUND:Preterm and small for gestational age (SGA) births have been associated with adverse outcomes during the first stages of life. We evaluated the morbidity and mortality associated with preterm and SGA births during the first year of life in a rural area of Southern Mozambique. METHODS:This is a retrospective cohort study using previously collected data from children born at the Manhiça District Hospital in two different periods (2003-2005 and 2010-2012). Newborns were classified as being preterm and/or SGA or as babies not fulfilling any of the previous conditions (term non-SGA). All children were followed up for a year for morbidity and mortality outcomes. RESULTS:A total of 5574 live babies were included in the analysis. The prevalence of preterm delivery was 6.2% (345/5574); the prevalence of SGA was 14.0% (776/5542) and 2.2% (114/5542) of the children presented both conditions. During the neonatal period, preterm delivery and SGA were associated with 13 (HR: 13.0, 95% CI 4.0-42.2) and 5 times (HR: 4.5, 95% CI: 1.6-12.6) higher mortality compared to term non SGA babies. Risk of hospitalization was only increased when both conditions were present (IRR: 3.5, 95%CI: 1.5-8.1). Mortality is also increased during the entire first year, although at a lower rate. CONCLUSIONS:Neonatal and infant mortality rates are remarkably high among preterm and SGA babies in southern Mozambique. These increased rates are concentrated within the neonatal period. Prompt identification of these conditions is needed to implement interventions aimed at increasing survival of these high-risk newborns.

Fundamentos: La migración ha contribuido a la emergencia de ciertas enfermedades infecciosas en los países receptores de inmigrantes. En España el número de inmigrantes ha crecido exponencialmente en las últimas décadas. El objetivo de esta revisión es identificar y analizar la información disponible sobre parasitosis importadas en población inmigrante en nuestro país. Métodos: Revisión de conjunto de artículos originales publicados sobre parasitosis importadas publicados entre 1998 y 2012. Se incluyeron trabajos realizados con poblaciones procedentes de Latinoamérica, África, Asia y Europa del Este o que cumplieran la definición de inmigrante de la Organización Internacional de Migraciones. La búsqueda bibliográfica se realizó en Medline y MEDES-Medicina. Resultados: Se incluyó un total de 51 estudios descriptivos en el análisis. La mayor parte de los inmigrantes atendidos procedieron del África Subsahariana (16%-87% según estudios), seguidos de América Latina(13%-37%), siendo Asia la región menos representada (0,2%-8,8%). Destaca que el 6,5-31% de los inmigrantes atendidos en unidades de medicina tropical o de atención al inmigrante y procedentes de América Latina, en particular de Bolivia, están afectados por la enfermedad de Chagas y la existencia en nuestro país de casos de transmisión congénita de esta enfermedad. Conclusiones: Las parasitosis importadas son un diagnóstico frecuente entre la población inmigrante. Esta revisión pone de manifiesto el impacto que ha tenido la migración en la emergencia de ciertas enfermedades parasitarias importadas, siendo un ejemplo paradigmático la enfermedad de Chagas.

P. vivax infection during pregnancy has been associated with poor outcomes such as anemia, low birth weight and congenital malaria, thus representing an important global health problem. However, no vaccine is currently available for its prevention. Vir genes were the first putative virulent factors associated with P. vivax infections, yet very few studies have examined their potential role as targets of immunity. We investigated the immunogenic properties of five VIR proteins and two long synthetic peptides containing conserved VIR sequences (PvLP1 and PvLP2) in the context of the PregVax cohort study including women from five malaria endemic countries: Brazil, Colombia, Guatemala, India and Papua New Guinea (PNG) at different timepoints during and after pregnancy. Antibody responses against all antigens were detected in all populations, with PNG women presenting the highest levels overall. P. vivax infection at sample collection time was positively associated with antibody levels against PvLP1 (fold-increase: 1.60 at recruitment -first antenatal visit-) and PvLP2 (fold-increase: 1.63 at delivery), and P. falciparum co-infection was found to increase those responses (for PvLP1 at recruitment, fold-increase: 2.25). Levels of IgG against two VIR proteins at delivery were associated with higher birth weight (27 g increase per duplicating antibody levels, p

BACKGROUND:Information on costs associated with malaria in pregnancy (MiP) in low transmission areas where Plasmodium vivax predominates is so far missing. This study estimates health system and patient costs of MiP in the Brazilian Amazon. METHODS/PRINCIPAL FINDINGS:Between January 2011 and March 2012 patient costs for the treatment of MiP were collected through an exit survey at a tertiary referral hospital and at a primary health care centre in the Manaus metropolitan area, Amazonas state. Pregnant and post-partum women diagnosed with malaria were interviewed after an outpatient consultation or at discharge after admission. Seventy-three interviews were included in the analysis. Ninety-six percent of episodes were due to P. vivax and 4% to Plasmodium falciparum. In 2010, the total median costs from the patient perspective were estimated at US $45.91 and US $216.29 for an outpatient consultation and an admission, respectively. When multiple P. vivax infections during the same pregnancy were considered, patient costs increased up to US $335.85, representing the costs of an admission plus an outpatient consultation. Provider direct and overhead cost data were obtained from several sources. The provider cost associated with an outpatient case, which includes several consultations at the tertiary hospital was US $103.51 for a P. vivax malaria episode and US $83.59 for a P. falciparum malaria episode. The cost of an inpatient day and average admission of 3 days was US $118.51 and US $355.53, respectively. Total provider costs for the diagnosis and treatment of all malaria cases reported in pregnant women in Manaus in 2010 (N = 364) were US $17,038.50, of which 92.4% (US$ 15,741.14) due to P. vivax infection. CONCLUSION:Despite being an area of low risk malaria transmission, MiP is responsible for a significant economic burden in Manaus. Especially when multiple infections are considered, costs associated with P. vivax are higher than costs associated with P. falciparum. The information generated may help health policy decisions for the current control and future elimination of malaria in the area.

BACKGROUND:Bangladesh has the highest rate of adolescent pregnancy in South Asia. Child marriage is one of the leading causes of pregnancies among adolescent girls. Although the country's contraceptive prevalence rate is quite satisfactory, only 52% of married adolescent girls use contraceptive methods. This qualitative study is aimed at exploring the factors that influence adolescent girls' decision-making process in relation to contraceptive methods use and childbearing. METHODS AND RESULTS:We collected qualitative data from study participants living in Rangpur district, Bangladesh. We conducted 35 in-depth interviews with married adolescent girls, 4 key informant interviews, and one focus group discussion with community health workers. Adolescent girls showed very low decision-making autonomy towards contraceptive methods use and childbearing. Decisions were mainly made by either their husbands or mothers-in-law. When husbands were unemployed and financially dependent on their parents, then the mothers-in-law played most important role for contraceptive use and childbearing decisions. Lack of reproductive health knowledge, lack of negotiation and communication ability with husbands and family members, and mistrust towards contraceptive methods also appeared as influential factors against using contraception resulting in early childbearing among married adolescent girls. CONCLUSIONS:Husbands and mothers-in-law of newly married adolescent girls need to be actively involved in health interventions so that they make more informed decisions regarding contraceptive use to delay pregnancies until 20 years of age. Misunderstanding and distrust regarding contraceptives can be diminished by engaging the wider societal actors in health intervention including neighbours, and other family members.

BACKGROUND:During pregnancy, syncytiotrophoblast vesicles contribute to maternal tolerance towards the fetus, but also to pathologies such as pre-eclampsia. The aim of the study was to address whether Plasmodium falciparum and HIV infections in pregnancy affect the secretion, microRNA content and function of trophoblast microparticles. METHODS:Microparticles were isolated and characterized from 122 peripheral plasmas of Mozambican pregnant women, malaria- and/or HIV-infected and non-infected. Expression of placenta-related microRNAs in microparticles was analysed by qPCR and the effect of circulating microparticles on dendritic cells assessed by phenotype analysis and cytokine/chemokine measurement. RESULTS:Concentrations of total and trophoblast microparticles detected by flow cytometry were higher in HIV-positive (P = 0.005 and P = 0.030, respectively) compared to non-infected mothers, as well as in women delivering low birthweight newborns (P = 0.032 and P = 0.021, respectively). miR-517c was overexpressed in mothers with placental malaria (P = 0.034), compared to non-infected. Microparticles from HIV-positive induced a higher expression of MHCII (P = 0.021) and lower production of MCP1 (P = 0.008) than microparticles from non-infected women. CONCLUSIONS:In summary, alterations in total and trophoblast microparticles associated with malaria and HIV in pregnant women may have an immunopathogenic role. The potential for placental-derived vesicles and microRNAs as biomarkers of adverse outcomes during pregnancy and malaria infection should be confirmed in future studies.

Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied.

INTRODUCTION:Plasmodium vivax is the most prevalent malaria species in the American region. Brazil accounts for the higher number of the malaria cases reported in pregnant women in the Americas. This study aims to describe the characteristics of pregnant women with malaria in an endemic area of the Brazilian Amazon and the risk factors associated with prematurity and low birth weight (LBW). METHODS/PRINCIPAL FINDINGS:Between December 2005 and March 2008, 503 pregnant women with malaria that attended a tertiary health centre were enrolled and followed up until delivery and reported a total of 1016 malaria episodes. More than half of study women (54%) were between 20-29 years old, and almost a third were adolescents. The prevalence of anaemia at enrolment was 59%. Most women (286/503) reported more than one malaria episode and most malaria episodes (84.5%, 846/1001) were due to P. vivax infection. Among women with only P. vivax malaria, the risk of preterm birth and low birth weight decreased in multigravidae (OR, 0.36 [95% CI, 0.16-0.82]; p = 0.015 and OR 0.24 [95% CI, 0.10-0.58]; p = 0.001, respectively). The risk of preterm birth decreased with higher maternal age (OR 0.43 [95% CI, 0.19-0.95]; p = 0.037) and among those women who reported higher antenatal care (ANC) attendance (OR, 0.32 [95% CI, 0.15-0.70]; p = 0.005). CONCLUSION:This study shows that P. vivax is the prevailing species among pregnant women with malaria in the region and shows that vivax clinical malaria may represent harmful consequences for the health of the mother and their offsprings particularly on specific groups such as adolescents, primigravidae and those women with lower ANC attendance.

Age- and exposure-dependent immune responses during a malaria episode may be key to understanding the role of these factors in the acquisition of immunity to malaria. Plasma/serum samples collected from naïve Mozambican children (n=48), European adults (naïve travelers, n=22; expatriates with few prior malaria exposures, n=15) and Mozambican adults with long-life malaria exposure (n=99) during and after a malaria episode were analyzed for IgG against merozoite proteins by Luminex and against infected erythrocytes by flow cytometry. Cytokines and chemokines were analyzed in plasmas/sera by suspension array technology. No differences were detected between children and adults with a primary infection, with the exception of higher IgG levels against 3D7 MSP-1(42) (P=0.030) and a P. falciparum isolate (P=0.002), as well as higher IL-12 (P=0.020) in children compared to other groups. Compared to malaria-exposed adults, children, travelers and expatriates had higher concentrations of IFN-γ (P ≤ 0.0090), IL-2 (P ≤ 0.0379) and IL-8 (P ≤ 0.0233). Children also had higher IL-12 (P=0.0001), IL-4 (P=0.003), IL-1β (P=0.024) and TNF (P=0.006) levels compared to malaria-exposed adults. Although IL-12 was elevated in children, overall the data do not support a role of age in immune responses to a first malaria episode. A T(H)1/pro-inflammatory response was the hallmark of non-immune subjects.

BackgroundMalaria immunity is commonly believed to wane in the absence of Plasmodium falciparum exposure, based on limited epidemiological data and short-lived antibody responses in some longitudinal studies in endemic areas.MethodsA cross-sectional study was conducted among sub-Saharan African adults residing in Spain for 1 up to 38 years (immigrants) with clinical malaria (n=55) or without malaria (n=37), naïve adults (travelers) with a first clinical malaria episode (n=20) and life-long malaria exposed adults from Mozambique (semi-immune adults) without malaria (n=27) or with clinical malaria (n=50). Blood samples were collected and IgG levels against the erythrocytic antigens AMA-1 and MSP-1₄₂ (3D7 and FVO strains), EBA-175 and DBL-α were determined by Luminex. IgG levels against antigens on the surface of infected erythrocytes (IEs) were measured by flow cytometry.ResultsImmigrants without malaria had lower IgG levels than healthy semi-immune adults regardless of the antigen tested (P≤0.026), but no correlation was found between IgG levels and time since migration. Upon reinfection, immigrants with malaria had higher levels of IgG against all antigens than immigrants without malaria. However, the magnitude of the response compared to semi-immune adults with malaria depended on the antigen tested. Thus, immigrants had higher IgG levels against AMA-1 and MSP-1₄₂ (P≤0.015), similar levels against EBA-175 and DBL-α, and lower levels against IEs (P≤0.016). Immigrants had higher IgG levels against all antigens tested compared to travelers (P≤0.001), both with malaria.ConclusionsUpon cessation of malaria exposure, IgG responses to malaria-specific antigens were maintained to a large extent, although the conservation and the magnitude of the recall response depended on the nature of the antigen. Studies on immigrant populations can shed light on the factors that determine the duration of malaria specific antibody responses and its effect on protection, with important implications for future vaccine design and public health control measures.

Immunity to malaria is believed to wane with time in the absence of exposure to Plasmodium falciparum infection, but immunoepidemiological data on longevity of immunity remain controversial. We quantified serum cytokines and chemokines by suspension array technology as potential biomarkers for durability of immunity in immigrants with clinical malaria after years without parasite exposure. These were compared to serum/plasma profiles in naïve adults (travelers) and semi-immune adults under continuous exposure, with malaria, along with immigrant and traveler patients without malaria. Immigrants had higher levels of IL-2, IL-5 and IL-8 compared to semi-immune adults with malaria (P≤0.0200). Time since immigration correlated with increased IL-2 (rho=0.2738P=0.0495) and IFN-γ (rho=0.3044P=0.0282). However, immigrants did not show as high IFN-γ concentrations as travelers during a first malaria episode (P

Plasmodium falciparum infected erythrocytes (IE) accumulate in the placenta through the interaction between Duffy-binding like (DBL) domains of parasite-encoded ligand VAR2CSA and chondroitin sulphate-A (CSA) receptor. Polymorphisms in these domains, including DBL2X and DBL3X, may affect their antigenicity or CSA-binding affinity, eventually increasing parasitemia and its adverse effects on pregnancy outcomes. A total of 373 DBL2X and 328 DBL3X sequences were obtained from transcripts of 20 placental isolates infecting Mozambican women, resulting in 176 DBL2X and 191 DBL3X unique sequences at the protein level. Sequence alignments were divided in segments containing combinations of correlated polymorphisms and the association of segment sequences with placental parasite density was tested using Bonferroni corrected regression models, taking into consideration the weight of each sequence in the infection. Three DBL2X and three DBL3X segments contained signatures of high parasite density (P

BACKGROUND: Plasmodium vivax can potentially lead to life-threatening episodes but the mechanisms underlying severe disease remain poorly defined. Cytoadhesion of infected erythrocytes may contribute to P. vivax sequestration and organ injury although its physiological impact is still unknown. Here, we aimed to describe clinically-relevant cytoadhesive phenotypes of P. vivax isolates. METHODOLOGY/PRINCIPAL FINDINGS: Rosetting and adhesion to CSA, CD36, ICAM1, placental and brain cryosections were determined in P. vivax peripheral isolates from 12 pregnant women, 24 non-pregnant women and 23 men from Manaus (Brazil). P. falciparum co-infection was excluded by PCR and P. vivax isolates were genotyped by assessing the size polymorphism of microsatellites ms2, ms20 and msp1F3 through capillary electrophoresis of PCR products. P. vivax monoinfection was confirmed by PCR in 59 isolates, with 50 (85%) of them being single-clone infections. One P. vivax haplotype was more frequently found among pregnant women (33%) than in non-pregnant women (0%) and men (4%; p=0.010). Rosetting was observed in 64% of the isolates, adhesion to CSA in 15%, to ICAM1 in 12% and to placental cryosections in 9%, being similar among pregnant and non-pregnant groups. Intensity of rosetting was higher among anaemic individuals compared to non-anaemic (p=0.010) and decreased with increasing haematocrit (p=0.033) and haemoglobin levels (p=0.015). CONCLUSIONS/SIGNIFICANCE: P. vivax peripheral isolates from pregnant women do not exhibit a prominent adhesion to CSA, although other parasite phenotypes still unknown may increase the propagation of certain P. vivax clones observed among pregnant hosts. Rosetting is a frequent cytoadhesive phenotype in P. vivax infections that may contribute to the development of anaemia.

BackgroundLow Birth Weight (LBW) is prevalent in low-income countries. Even though the economic evaluation of interventions to reduce this burden is essential to guide health policies, data on costs associated with LBW are scarce. This study aims to estimate the costs to the health system and to the household and the Disability Adjusted Life Years (DALYs) arising from infant deaths associated with LBW in Southern Mozambique.Methods and findingsCosts incurred by the households were collected through exit surveys. Health system costs were gathered from data obtained onsite and from published information. DALYs due to death of LBW babies were based on local estimates of prevalence of LBW (12%), very low birth weight (VLBW) (1%) and of case fatality rates compared to non-LBW weight babies [for LBW (12%) and VLBW (80%)]. Costs associated with LBW excess morbidity were calculated on the incremental number of hospital admissions in LBW babies compared to non-LBW weight babies. Direct and indirect household costs for routine health care were 24.12 US$ (CI 95% 21.51; 26.26). An increase in birth weight of 100 grams would lead to a 53% decrease in these costs. Direct and indirect household costs for hospital admissions were 8.50 US$ (CI 95% 6.33; 10.72). Of the 3,322 live births that occurred in one year in the study area, health system costs associated to LBW (routine health care and excess morbidity) and DALYs were 169,957.61 US$ (CI 95% 144,900.00; 195,500.00) and 2,746.06, respectively.ConclusionsThis first cost evaluation of LBW in a low-income country shows that reducing the prevalence of LBW would translate into important cost savings to the health system and the household. These results are of relevance for similar settings and should serve to promote interventions aimed at improving maternal care.

Malaria in pregnancy is a public health problem for endemic countries. Economic evaluations of malaria preventive strategies in pregnancy are needed to guide health policies.This analysis was carried out in the context of a trial of malaria intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP), where both intervention groups received an insecticide treated net through the antenatal clinic (ANC) in Mozambique. The cost-effectiveness of IPTp-SP on maternal clinical malaria and neonatal survival was estimated. Correlation and threshold analyses were undertaken to assess the main factors affecting the economic outcomes and the cut-off values beyond which the intervention is no longer cost-effective. In 2007 US$, the incremental cost-effectiveness ratio (ICER) for maternal malaria was 41.46 US$ (95% CI 20.5, 96.7) per disability-adjusted life-year (DALY) averted. The ICER per DALY averted due to the reduction in neonatal mortality was 1.08 US$ (95% CI 0.43, 3.48). The ICER including both the effect on the mother and on the newborn was 1.02 US$ (95% CI 0.42, 3.21) per DALY averted. Efficacy was the main factor affecting the economic evaluation of IPTp-SP. The intervention remained cost-effective with an increase in drug cost per dose up to 11 times in the case of maternal malaria and 183 times in the case of neonatal mortality.IPTp-SP was highly cost-effective for both prevention of maternal malaria and reduction of neonatal mortality in Mozambique. These findings are likely to hold for other settings where IPTp-SP is implemented through ANC visits. The intervention remained cost-effective even with a significant increase in drug and other intervention costs. Improvements in the protective efficacy of the intervention would increase its cost-effectiveness. Provision of IPTp with a more effective, although more expensive drug than SP may still remain a cost-effective public health measure to prevent malaria in pregnancy.ClinicalTrials.gov NCT00209781.

In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association.In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP.There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136). There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041). Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039). IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%); p = 0.024].Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health.ClinicalTrials.gov NCT00209781.

Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets (ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of their combined use.1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC) visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess the safety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight.Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence at delivery (RR, 0.92 [95% CI, 0.79-1.08]), low birth weight (RR, 0.99 [95% CI, 0.70-1.39]), or overall placental infection (p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40-61.20]; p = 0.020) in the incidence of clinical malaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p