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Background Survivors of invasive group B Streptococcus (iGBS) disease, notably meningitis, are at increased risk of neurodevelopmental impairment. However, the limited studies to date have a median follow-up to 18 months and have mainly focused on moderate or severe neurodevelopmental impairment, with no previous studies on emotional-behavioral problems among iGBS survivors. Methods In this multicountry, matched cohort study, we included children aged 18 months to 17 years with infant iGBS sepsis and meningitis from health demographic surveillance systems, or hospital records in Argentina, India, Kenya, Mozambique, and South Africa. Children without an iGBS history were matched to iGBS survivors for sex and age. Our primary outcomes were emotional-behavioral problems and psychopathological conditions as measured with the Child Behavior Checklist (CBCL). The CBCL was completed by the child’s primary caregiver. Results Between October 2019 and April 2021, 573 children (mean age, 7.18 years) were assessed, including 156 iGBS survivors and 417 non-iGBS comparison children. On average, we observed more total problems and more anxiety, attention, and conduct problems for school-aged iGBS survivors compared with the non-iGBS group. No differences were found in the proportion of clinically significant psychopathological conditions defined by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Conclusions Our findings suggested that school-aged iGBS survivors experienced increased mild emotional behavioral problems that may affect children and families. At-risk neonates including iGBS survivors need long-term follow-up with integrated emotional-behavioral assessments and appropriate care. Scale-up will require simplified assessments that are free and culturally adapted.

Background Invasive group B Streptococcus disease (iGBS) in infancy, including meningitis or sepsis, carries a high risk of mortality and neurodevelopmental impairment (NDI). We present data on iGBS from 2 decades of surveillance in Manhiça, Mozambique, with a focus on NDI. Methods Morbidity surveillance databases in a rural Mozambican district hospital were screened for iGBS cases. From February 2020 to March 2021, surviving iGBS patients (n = 39) plus age- and sex-matched children without iGBS (n = 119) were assessed for neurocognitive development, vision, and hearing. The role of GBS in stillbirths and infant deaths was investigated using minimally invasive tissue sampling (MITS). Results Ninety iGBS cases were included, with most children being Conclusions In absence of preventive strategies, such as intrapartum antibiotics, iGBS remains a significant cause of perinatal and infant disease and death. GBS also causes major longer-term neurodevelopmental sequelae, altogether justifying the need for maternal GBS vaccination strategies to increase perinatal and infant survival.

In their roles as nurses, data collectors, or other, fieldworkers undertake myriad tasks working intimately with and on the bodies of others–a type of work called ‘body work’. This work further includes the micro-political relations shaping these interactions, and studies have shown the importance of these relationships in the success of clinical trials, particularly in the Gambia. This study seeks to expand the concept of body work to understand the roles and interactions of fieldworkers within the trial community, and the effect on a mass drug administration (MDA) clinical trial. We conducted a mixed-methods social science study alongside the MDA in 2018–2019, including in-depth interviews, focus group discussions, and semi-structured observations with the population involved (and not) in the MDA, as well as the MRC fieldworkers. We found that fieldworkers participated in what we call ‘reciprocity work’. Through their regular tasks and interactions, they necessarily showed respect and established trust in a way that formed and contributed to reciprocal relationships, the results of which impacted the trial and individuals’ autonomy in the decision-making process. Understanding the role of fieldworkers and their reciprocity work is a vital component in comprehending how research ethics are made and conducted in global health research.

INTRODUCTION: Pertussis is a highly contagious respiratory disease that results in disproportionate morbidity and mortality in infants who have yet to receive the primary diphtheria-tetanus-pertussis vaccine series. In the preceding decades numerous countries started to pursue either prenatal vaccination of pregnant women or postpartum vaccination of caregivers to protect infants. Despite proven benefit, maternal uptake of pertussis vaccine continues to be suboptimal. AREAS COVERED: Many studies have been conducted to address the suboptimal uptake of maternal pertussis vaccination. This systematic review was undertaken to systematically identify those studies, highlight the most successful strategies and find the knowledge gaps that need to be filled over the coming years to improve vaccine uptake. Twenty-five studies were identified from six different databases. EXPERT COMMENTARY: Five different interventions were shown to be successful in promoting uptake of pertussis vaccination: (1) standing orders, (2) opt-in orders, (3) provider education, (4) on-site vaccination and (5) interactive patient education. Three major knowledge gaps were also identified that need to be filled over the coming years: (1) lack of studies in low- and middle-income countries, (2) lack of studies targeting midwives and/or home birth and (3) lack of studies on the process of vaccine communication.

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 < 0.05) concentrations. Eotaxin-2 concentrations in the malaria-exposed non-pregnant group were significantly lower than the in the malaria-naive non-pregnant and the malaria-exposed pregnant groups. Eotaxin-3 plasma concentrations were lower in malaria-exposed than in non-exposed groups (p < 0.05), but no differences were found associated to pregnancy. Eotaxin-2 and eotaxin-3 plasma concentrations were negatively correlated with anti-Plasmodium IgG levels: PfDBL5ε-IgG ( rhoEo2 = − 0.35, p = 0.005; rhoEo3 =− 0.37, p = 0.011), and eotaxin-3 was negatively correlated with PfDBL3x-IgG levels ( rhoEo3 =− 0.36; p = 0.011). Negative correlations of eotaxin-2 and 3 in plasma were also observed with atypical memory B cells ( rhoEo2 = − 0.37, p < 0.001; rhoEo3= − 0.28, p = 0.006), a B cell subset expanded in malaria-exposed individuals. In addition, a borderline negative association was observed between eotaxin-3 concentrations and Plasmodium infection (adjusted effect estimate, β = − 0.279, 95% CI − 0.605; 0.047, p = 0.091). Moreover, eotaxin-2 placental concentrations were significantly increased compared to peripheral concentrations in the malariaexposed pregnant group whereas the contrary was observed in the non-exposed pregnant group (p < 0.005). Conclusion: Although a clear epidemiological negative association is observed between eotaxins concentrations and malaria exposure and/or infection, pregnancy may alter this association for eotaxin-2. Further research is required to understand the role of these chemokines in this disease and in combination with pregnancy., European Commission PREGVAX FP7-EALTH-201588, Malaria in Pregnancy Consortium (MiPc) through Bill & Melinda Gates Foundation 46099, Government of Spain, Ramon y Cajal Fellowship RYC-2013-14512, State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program CEX2018-000806-S, Generalitat de Catalunya through the CERCA Program, Fundacion Ramon Areces, Ministry of Science and Innovation, Spain (MICINN), Spanish Government

Zika virus (ZIKV) infection during pregnancy is a cause of pregnancy loss and multiple clinical and neurological anomalies in children. This systematic review aimed to assess the effect of ZIKV exposure in utero on the long-term neurodevelopment of normocephalic children born to women with ZIKV infection in pregnancy. This review was conducted according to the PRISMA guidelines for systematic reviews and meta-analyses. We performed a random effects meta-analysis to estimate the cross-study prevalence of neurodevelopmental delays in children using the Bayley Scales for Infant and Toddler Development (BSID-III). The risk of bias was assessed using Cochrane’s Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Full-text reviews were performed for 566 articles, and data were extracted from 22 articles corresponding to 20 studies. Nine articles including data from 476 children found 6.5% (95% CI: 4.1–9.3) of infants and children to have any type of non-language cognitive delay; 29.7% (95% CI: 21.7–38.2) to have language delay; and 11.5% (95% CI: 4.8–20.1) to have any type of motor delay. The pooled estimates had a high level of heterogeneity; thus, results should be interpreted with caution. Larger prospective studies that include a non-exposed control group are needed to confirm whether ZIKV exposure in utero is associated with adverse child neurodevelopmental outcomes.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval ( from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

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.

Data are limited regarding long-term consequences of invasive GBS (iGBS) disease in early infancy, especially from low- and middle-income countries (LMIC) where most cases occur. We aimed to estimate risk of neurodevelopmental impairment (NDI) in children with a history of iGBS disease.A multi-country matched cohort study was undertaken in South Africa, India, Mozambique, Kenya, and Argentina from October 2019 to April 2021. The exposure of interest was defined as a history of iGBS disease (sepsis or meningitis) before 90 days of age, amongst children now aged 1·5-18 years. Age and sex-matched, children without history of GBS were also recruited. Age-appropriate, culturally-adapted assessments were used to define NDI across multiple domains (cognitive, motor, hearing, vision, emotional-behaviour, growth). Pooled NDI risk was meta-analysed across sites. Association of iGBS exposure and NDI outcome was estimated using modified Poisson regression with robust variance estimator.Amongst 138 iGBS survivors and 390 non-iGBS children, 38·1% (95% confidence interval [CI]: 30·0% - 46·6%) of iGBS children had any NDI, compared to 21·7% (95% CI: 17·7% - 26·0%) of non- iGBS children, with notable between-site heterogeneity. Risk of moderate/severe NDI was 15·0% (95% CI: 3·4% - 30·8%) among GBS-meningitis, 5·6% (95% CI: 1·5% - 13·7%) for GBS-sepsis survivors. The adjusted risk ratio (aRR) for moderate/severe NDI among iGBS survivors was 1.27 (95% CI: 0.65, 2.45), when compared to non-GBS children. Mild impairment was more frequent in iGBS (27.6% (95% CI: 20.3 - 35.5%)) compared to non-GBS children (12.9% (95% CI: 9.7% - 16.4%)). The risk of emotional-behavioural problems was similar irrespective of iGBS exposure (aRR=0.98 (95% CI: 0.55, 1.77)).Our findings suggest that iGBS disease is on average associated with a higher risk of moderate/severe NDI, however substantial variation in risk was observed between sites and data are consistent with a wide range of values. Our study underlines the importance of long-term follow-up for at-risk neonates and more feasible, standardised assessments to facilitate diagnosis in research and clinical practice.This work was supported by a grant (INV-009018) from the BillMelinda Gates Foundation to the London School of HygieneTropical Medicine.

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

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) transmitted primarily by Aedes mosquitoes. ZIKV can be transmitted to humans by non-vector borne mechanisms such as sexual intercourse, maternal-foetal transmission or blood transfusion. In 2015, ZIKV emerged in the Americas, and spread to 87 countries and territories with autochthonous transmission, distributed across four of the six WHO regions. Most ZIKV infections in pregnancy are asymptomatic, but mother to child transmission of the virus can occur in 20 to 30% of cases and cause severe foetal and child defects. Children exposed to ZIKV while in utero might develop a pattern of structural anomalies and functional disabilities secondary to central nervous system damage, known as congenital Zika syndrome, and whose most common clinical feature is microcephaly. Normocephalic children born to mothers with ZIKV infection in pregnancy, and with no observable Zika-associated birth defects, may also present with later neurodevelopmental delay or post-natal microcephaly. Screening and detection of ZIKV infection in pregnancy is essential, because most women with ZIKV infection are asymptomatic and clinical manifestations are non-specific. However, the diagnosis of ZIKV infection poses multiple challenges due to limited resources and scarce laboratory capabilities in most affected areas, the narrow window of time that the virus persists in the bloodstream, the large proportion of asymptomatic infections, and the cross-reactivity with other flaviviruses such as Dengue virus (DENV). Molecular methods (RT-PCR) are the most reliable tool to confirm ZIKV infection, as serodiagnosis requires confirmation with neutralization tests in case of inconclusive or positive serology results. Prenatal ultrasound assessment is essential for monitoring foetal development and early detection of possible severe anomalies. A mid- and long-term follow-up of children exposed to ZIKV while in utero is necessary to promptly detect clinical manifestations of possible neurological impairment. Tweetable abstract: Zika virus infection during pregnancy is a cause of pregnancy loss and disability in children. Protection against mosquito bites, access to sexual and reproductive health services, prompt screening and detection of ZIKV infection in pregnancy, and prenatal ultrasound monitoring are key control strategies whilst a vaccine is not available.

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.

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. post-print 449 KB

Background Mozambique has one of the highest cervical cancer incidence rates in the world. Health interventions are still being conceived from a non-communicable disease standpoint despite it being a sexual and reproductive health concern. The objective of this study was to assess the extent to which lay perceptions of cervical cancer align with biomedical knowledge from the standpoint of sexual and reproductive health.Methods 10 FGD were carried out with 10 target groups in Manhiça. The target groups were diverse and ranged from of adolescent girls to informal drug vendors. There were a total of 116 participants. The FGD were used to obtain verbal information and trigger debates around beliefs and attitudes about cervical cancer as well as to explore notions of transmission and aetiology of the disease. The discussions were recorded for later transcription and analysis, following a combination of content and thematic analysis.Results Participants were familiar with the biomedical term ‘cervical cancer’ but knowledge of its aetiology and transmission was limited. Cervical cancer was readily associated to sexual transmission and sexually transmitted infections, and conceived as a ‘wound that doesn’t heal’. The term ‘cancer’ caused confusion, as it was perceived to happen only in limbs, understood as hereditary, not transmissible and as an illness of the West.Conclusions Lay perceptions of cervical cancer do to a large extent align with biomedical ones, thus, there is common ground to frame future health interventions from a sexual and reproductive health standpoint.

The emergence of Zika virus (ZIKV) represents a threat with consequences on maternal and children's health. We aimed to assess the clinical and epidemiological characteristics of pregnant women returning from ZIKV affected areas, and the effects of maternal ZIKV infection on birth outcomes and children's health. This was a hospital-based prospective observational study conducted at the Hospital Clínic of Barcelona and Hospital Sant Joan de Déu, Barcelona, Spain, from January 2016 to February 2020. One hundred and ninety-five pregnant women who had travelled to ZIKV affected areas during pregnancy were recruited. Four women (2.1%) had a confirmed ZIKV infection, 40 women (20.5%) a probable infection, and 151 (77.4%) were negative for ZIKV. Among the ZIKV confirmed cases, a pregnant woman suffered a miscarriage, highly plausible to be associated with ZIKV infection. Brain cysts and microcalcifications were detected in 7% of fetuses or infants from women with confirmed or probable ZIKV infection. Neurodevelopmental delay in the language function was found in 33.3% out of the 21 children evaluated. These findings contribute to the understanding of ZIKV prevalence estimates, and the impact of maternal ZIKV infection on pregnancy outcomes and children's health. Results highlight the importance of long-term surveillance in pregnant travellers and their children. This work was supported by the Government of Spain [grant number PI16/0123, ISCIII-AES Proyectos de Investigación en Salud, 2016]; a predoctoral fellowship from “la Caixa” Foundation (ID 100010434) [fellowship LCF/BQ/ES17/11600006]; the Ministry of Science, Innovation and Universities, Government of Spain through a Ramon y Cajal Grant [RYC-2013-14,512]; RICET, a Tropical Disease Cooperative Research Network in Spain [RD12/0018/0010] cofounded by ISCIII and the Fondo Europeo de Desarrollo Regional (FEDER); the Departament d’Universitats I Recerca de la Generalitat de Catalunya, Spain, AGAUR [grant 2017SGR924]; and ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Sí

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.

BACKGROUND: Mandatory vaccination has been effective in maintaining high vaccination coverage in countries such as the United States. However, there are no peer-reviewed analyses of the association between mandates and both coverage and subsequent incidence of vaccine-preventable disease in Europe. METHODS: Using data from the European Centre for Disease Prevention and Control and the World Health Organization, we evaluated the relationship between country-level mandatory vaccination policies and (1) measles and pertussis vaccine coverage and (2) the annual incidence of these diseases in 29 European countries. Multivariate negative binomial and linear regression models were used to quantify these associations. RESULTS: Mandatory vaccination was associated with a 3.71 (95% confidence interval [CI]: 1.68 to 5.74) percentage point higher prevalence of measles vaccination and a 2.14 (95% CI: 0.13 to 4.15) percentage point higher prevalence of pertussis vaccination when compared with countries that did not have mandatory vaccination. Mandatory vaccination was only associated with decreased measles incidence for countries without nonmedical exemptions (adjusted incidence rate ratio = 0.14; 95% CI: 0.05 to 0.36). We did not find a significant association between mandatory vaccination and pertussis incidence. CONCLUSIONS: Mandatory vaccination and the magnitude of fines were associated with higher vaccination coverage. Moreover, mandatory vaccination was associated with lower measles incidence for countries with mandatory vaccination without nonmedical exemptions. These findings can inform legislative policies aimed at increasing vaccination coverage.

The immune status of women changes during and after pregnancy, differs between blood compartments at delivery and is affected by environmental factors particularly in tropical areas endemic for multiple infections. We quantified the plasma concentration of a set of thirty-one TH1, TH2, TH17 and regulatory cytokines, pro-inflammatory and anti-inflammatory cytokines and chemokines, and growth factors (altogether biomarkers), in a cohort of 540 pregnant women from five malaria-endemic tropical countries. Samples were collected at recruitment (first antenatal visit), delivery (periphery, cord and placenta) and postpartum, allowing a longitudinal analysis. We found the lowest concentration of biomarkers at recruitment and the highest at postpartum, with few exceptions. Among them, IL-6, HGF and TGF-β had the highest levels at delivery, and even higher concentrations in the placenta compared to peripheral blood. Placental concentrations were generally higher than peripheral, except for eotaxin that was lower. We also compared plasma biomarker concentrations between the tropical cohort and a control group from Spain at delivery, presenting overall higher biomarker levels the tropical cohort, particularly pro-inflammatory cytokines and growth factors. Only IL-6 presented lower levels in the tropical group. Moreover, a principal component analysis of biomarker concentrations at delivery showed that women from Spain grouped more homogenously, and that IL-6 and IL-8 clustered together in the tropical cohort but not in the Spanish one. Plasma cytokine concentrations correlated with Plasmodium antibody levels at postpartum but not during pregnancy. This basal profiling of immune mediators over gestation and in different compartments at delivery is important to subsequently understand response to infections and clinical outcomes in mothers and infants in tropical areas.

Maternal immunization provides an excellent evidence-based strategy for preventing severe disease and decreasing neonatal and infant mortality. A substantial proportion of these deaths are due to infectious diseases, most of them vaccine-preventable, then, there is a real opportunity for intervention. Maternal immunization has been an underexploited area for many years, with the exception of neonatal tetanus. There are now programs for influenza and acellular pertussis vaccination in many countries and two maternal vaccine targets under development are focused on decreasing the burden of infant respiratory syncytial virus (RSV) and Group B Streptococcus (GBS). Bodies like the Strategic Advisory Group of Experts (SAGE) on Immunization established by the WHO, the Global Vaccine Action Plan (GVAP) and Gavi, The Vaccine Alliance, have recognized the relevance of maternal immunization on several occasions. However, why is the field not moving faster, as one might expect? Major initiatives and programs should consider spelling out more clearly the role and benefits of this intervention and calling for specific actions, including future strategic approaches for the post 2020 immunization strategy following the GVAP; and single out the area as one of its priorities as a key component of immunization across the life course. While waiting for the new vaccines like RSV and GBS and optimizing the use of influenza and pertussis there is momentum now to coordinate efforts, address the missing information and action gaps, and call to accelerate progress.

Dear editor: A recent editorial in Travel Medicine and Infectious Diseases highlighted the lack of studies about Zika virus (ZIKV) in pregnancy and its implications in many countries [1]. Zika virus infection can induce congenital defects in the newborn such as microcephaly and miscarriage when mothers are infected during pregnancy [2]. However, relevant questions remain to be completely understood, such as the risk of infection for pregnant women and of subsequent congenital defects, and the ratio between symptomatic and asymptomatic ZIKV infections in the general population and in pregnant women. Here, we describe the results of a ZIKV screening of pregnant women in Catalonia, northeastern Spain. Testing for ZIKV was recommended for all pregnant women with history of travel to ZIKV endemic areas during pregnancy or in the 8 weeks before conception [3]. Symptomatic patients were screened by serological methods from day four after the onset of symptoms and by molecular methods within the first week (serum) and two weeks (urine) after illness. Asymptomatic patients were tested by serological methods. Seroneutralization assay for ZIKV was perfomed in samples positive for antibodies. Commercial diagnostic assays were used (RT-PCR, Altona Diagnostics and IIFT, Euroimmun). Neutralization titers ≥1/32 were considered indicative of the presence of ZIKV neutralizing antibodies. Follow up at two designated reference obstetrical departments for early detection of microcephaly or other malformations was offered to pregnant women with laboratory evidence of ZIKV infection. When available, amniotic fluid and placental tissue samples were tested for ZIKV by RT-PCR in cases of microcephaly or miscarriage, respectively.

Zika virus (ZIKV) can cause pregnancy loss and congenital Zika syndrome, among other poor health outcomes. The ZIKV epidemic in 2015&ndash, 2017 disproportionately affected pregnant women in poor-resource settings. We aimed to understand perceptions and attitudes towards a hypothetical ZIKV vaccine, women&rsquo, 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&rsquo, 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.

Pregnant women are one of the most susceptible and vulnerable groups to malaria, the most important parasitic disease worldwide. Artemisinin-based combination therapies (ACTs) are recommended for the treatment of uncomplicated malaria in all population groups including pregnant women. However, due to the embryotoxicity observed in animal studies, ACTs have long been contraindicated during the first trimester in pregnant women. Despite the safety concerns raised in pre-clinical studies, recent findings on ACTs's use in pregnant women appear to be reassuring regarding safety and have prompted a revision of malaria treatment guidelines for first trimester of pregnancy. To contribute to the risk-benefit assessment of ACTs, we conducted a systematic literature review of animal studies published between 2007 and 2019, which evaluated the embryotoxic effects of artemisinin and its derivatives among pregnant mammals. Eighteen experimental studies fitted the inclusion criteria. These studies confirmed and further characterized the severe embryolethal and embryotoxic dose-dependent effects of artemisinin and its derivatives when administered during the organogenesis period in rats, rabbits and monkeys. Timing of administration and dosage of the drug were found to be key factors in the appearance of embryo damage. Overall, the translation of the findings of artemisinin derivatives use in animal studies to pregnant women remains disturbing. Thus, a policy change in the use of ACTs during the first trimester in pregnant women for the treatment of uncomplicated malaria does not seem pertinent and if implemented, it should be accompanied by solid pharmacovigilance systems, which are challenging to establish in malaria endemic countries.

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 (IL10) 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., European Union Seventh Framework Programme (FP7/2007-2013) 201588, Ministerio de Economia y Competitividad (National R&D Internationalization Programme, EUROSALUD 2008, Spain) EUS2009-03560, Centers for Disease Control and Prevention (CDC) Foundation, Malaria in Pregnancy Consortium (MiPc) - Bill & Melinda Gates Foundation 46099, MiPc, Spanish Government RYC-2008-02631, National Health and Medical Research Council of Australia GNT1043345

BACKGROUND Digital innovations have shown promise for improving maternal health service delivery. However, low- and middle-income countries are still at the adoption-utilization stage. Evidence on mobile health has been described as a black box, with gaps in theoretical explanations that account for the ecosystem of health care and their effect on adoption mechanisms. Bliss4Midwives, a modular integrated diagnostic kit to support antenatal care service delivery, was piloted for 1 year in Northern Ghana. Although both users and beneficiaries valued Bliss4Midwives, results from the pilot showed wide variations in usage behavior and duration of use across project sites. OBJECTIVE To strengthen the design and implementation of an improved prototype, the study objectives were two-fold: to identify causal factors underlying the variation in Bliss4Midwives usage behavior and understand how to overcome or leverage these in subsequent implementation cycles. METHODS Using a multiple case study design, a realist evaluation of Bliss4Midwives was conducted. A total of 3 candidate program theories were developed and empirically tested in 6 health facilities grouped into low and moderate usage clusters. Quantitative and qualitative data were collected and analyzed using realist thinking to build configurations that link intervention, context, actors, and mechanisms to program outcomes, by employing inductive and deductive reasoning. Nonparametric t test was used to compare the perceived usefulness and perceived ease of use of Bliss4Midwives between usage clusters. RESULTS We found no statistically significant differences between the 2 usage clusters. Low to moderate adoption of Bliss4Midwives was better explained by fear, enthusiasm, and high expectations for service delivery, especially in the absence of alternatives. Recognition from pregnant women, peers, supervisors, and the program itself was a crucial mechanism for device utilization. Other supportive mechanisms included ownership, empowerment, motivation, and adaptive responses to the device, such as realignment and negotiation. Champion users displayed high adoption-utilization behavior in contexts of participative or authoritative supervision, yet used the device inconsistently. Intervention-related (technical challenges, device rotation, lack of performance feedback, and refresher training), context-related (staff turnover, competing priorities, and workload), and individual factors (low technological self-efficacy, baseline knowledge, and internal motivation) suppressed utilization mechanisms. CONCLUSIONS This study shed light on optimal conditions necessary for Bliss4Midwives to thrive in a complex social and organizational setting. Beyond usability and viability studies, advocates of innovative technologies for maternal care need to consider how implementation strategies and contextual factors, such as existing collaborations and supervision styles, trigger mechanisms that influence program outcomes. In addition to informing scale-up of the Bliss4Midwives prototype, our results highlight the need for interventions that are guided by research methods that account for complexity.

INTRODUCTION: Recently, there has been a steady increase in mobile health (mHealth) interventions aimed at improving maternal health of women in low-income and middle-income countries. While there is evidence indicating that these interventions contribute to improvements in maternal health outcomes, other studies indicate inconclusive results. This uncertainty has raised additional questions, one of which pertains to the role of targeting strategies in implementing mHealth interventions and the focus on pregnant women and health workers as target groups. This review aims to assess who is targeted in different mHealth interventions and the importance of targeting strategies in maternal mHealth interventions. METHODS AND ANALYSIS: We will search for peer-reviewed, English-language literature published between 1999 and July 2017 in PubMed, Web of Knowledge (Science Direct, EMBASE) and Cochrane Central Registers of Controlled Trials. The study scope is defined by the Population, Intervention, Comparison and Outcomes framework: P, community members with maternal or reproductive needs; I, electronic health or mHealth programmes geared at improving maternal or reproductive health; C, other non-electronic health or mHealth-based interventions; O, maternal health measures including family planning, antenatal care attendance, health facility delivery and postnatal care attendance. ETHICS AND DISSEMINATION: This study is a review of already published or publicly available data and needs no ethical approval. Review results will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42017072280.

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., Author summary Malaria in pregnancy is a harsh and undesirable illness and is the cause of adverse effects on birth outcomes and on the health of women and newborns. Despite the low transmission, the predominance of Plasmodium vivax over Plasmodium falciparum and free treatment, estimated costs incurred by pregnant women seeking malaria care in an endemic area of Northern Colombia are considerable. Importantly, these 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 in the area. Important advances may result from the current peace process, potentially able to support the efforts made since the 90s to reform the health system towards achieving universal health coverage. Within this context, the current study can inform malaria elimination initiatives in Colombia.

BACKGROUND Despite continued interest in the use of mobile health for improving maternal health outcomes, there have been limited attempts to identify relevant program theories. OBJECTIVES This study had two aims: first, to explicate the assumptions of program designers, which we call the program theory and second, to contrast this program theory with empirical data to gain a better understanding of mechanisms, facilitators, and barriers related to the program outcomes. METHODS To achieve the aforementioned objectives, we conducted a retrospective qualitative study of a text messaging (short message service) platform geared at improving individual maternal health outcomes in Uganda. Through interviews with program designers (n=3), we elicited 3 main designers’ assumptions and explored these against data from qualitative interviews with primary beneficiaries (n=26; 15 women and 11 men) and health service providers (n=6), as well as 6 focus group discussions with village health team members (n=50) who were all involved in the program. RESULTS Our study results highlighted that while the program designers’ assumptions were appropriate, additional mechanisms and contextual factors, such as the importance of incentives for village health team members, mobile phone ownership, and health system factors should have been considered. CONCLUSIONS Our results indicate that text messages could be an effective part of a more comprehensive maternal health program when context and system barriers are identified and addressed in the program theories.

Background: Migration has contributed to the emergence of certain infectious diseases in host countries. In Spain the number of immigrants has increased exponentially in recent decades. The aim of this review is to identify and analyze the available information on imported parasitic diseases in immigrant population in our country. Methods: A scope review of original articles published on imported parasitic diseases between 1998 and 2012. Study populations from Latin America, Africa, Asia, Eastern Europe and individuals who are under the definition of an immigrant from International Organization for Migration were included. The literature search was performed in the Medline and MEDES-MEDicina databases. Results: A total of 51 descriptive studies were included in the analysis. Most immigrants attended at referral health facilities were originally from sub-Saharan Africa (between 16%-87%), followed by Latin America (13%-37%), while Asia was the region less represented (0.2%-8.8%). A considerable proportion (6.5-31%) of inmigrants that attended to referal units of tropical medicine or inmigrant health, and that were originally from Latin America, particularly those from Bolivia, are affected by the Chagas disease, and several cases of mother-to-child transmission have been registered in our country. Conclusion: Imported parasitosis is a frequent diagnosis among migrant population. This review highlight the impact that migration has had on the emergence of certain imported parasitic diseases, being Chagas disease the most paradigmatic example.

Background 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. Methods and findings 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

A vaccine to eliminate malaria would need a multi-stage and multi-species composition to achieve robust protection, but the lack of knowledge about antigen targets and mechanisms of protection precludes the development of fully efficacious malaria vaccines, especially for Plasmodium vivax (Pv). Pregnant women constitute a risk population who would greatly benefit from a vaccine preventing the adverse events of Plasmodium infection during gestation. We hypothesized that functional immune responses against putative targets of naturally acquired immunity to malaria and vaccine candidates will be associated with protection against malaria infection and/or poor outcomes during pregnancy. We measured (i) IgG responses to a large panel of Pv and Plasmodium falciparum (Pf) antigens, (ii) the capacity of anti-Pv ligand Duffy binding protein (PvDBP) antibodies to inhibit binding to Duffy antigen, and (iii) cellular immune responses to two Pv antigens, in a subset of 1,056 pregnant women from Brazil, Colombia, Guatemala, India, and Papua New Guinea (PNG). There were significant intraspecies and interspecies correlations for most antibody responses (e.g., PfMSP119 versus PfAMA1, Spearman’s rho = 0.81). Women from PNG and Colombia had the highest levels of IgG overall. Submicroscopic infections seemed sufficient to boost antibody responses in Guatemala but not antigen-specific cellular responses in PNG. Brazil had the highest percentage of Duffy binding inhibition (p-values versus Colombia: 0.040; Guatemala: 0.047; India: 0.003, and PNG: 0.153) despite having low anti-PvDBP IgG levels. Almost all antibodies had a positive association with present infection, and coinfection with the other species increased this association. Anti-PvDBP, anti-PfMSP1, and anti-PfAMA1 IgG levels at recruitment were positively associated with infection at delivery (p-values: 0.010, 0.003, and 0.023, respectively), suggesting that they are markers of malaria exposure. Peripheral blood mononuclear cells from Pv-infected women presented fewer CD8+IFN-γ+ T cells and secreted more G-CSF and IL-4 independently of the stimulus used in vitro. Functional anti-PvDBP levels at recruitment had a positive association with birth weight (difference per doubling antibody levels: 45 g, p-value: 0.046). Thus, naturally acquired binding-inhibitory antibodies to PvDBP might confer protection against poor outcomes of Pv malaria in pregnancy.

Drug failure is a common cause of symptom persistence after treatment of imported Giardia duodenalis. In this retrospective study we describe a high prevalence of refractory giardiasis in people attended in a travel clinic in Spain, especially those with infections acquired in Asia. Moreover, we discuss various treatment strategies to tackle G. duodenalis that is refractory to nitroimidazoles.

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., Author Summary Malaria in pregnancy (MiP) is associated with maternal and foetal morbidity and mortality. In addition to the clinical burden, MiP implies a significant economic burden, but the little available evidence on the economics of MiP is limited to Plasmodium falciparum malaria and to the sub-Saharan region. While an increasing interest has been recently devoted to the epidemiology and the clinical consequences of Plasmodium vivax, the economics of P. vivax malaria is neglected. P. vivax is endemic in Latin America, and Brazil is the country with the highest reported burden of MiP of the American continent. Between 2011 and 2012, we conducted a study in the city of Manaus, Brazilian Amazon, with the aim of estimating costs associated with MiP both from the health provider and the patient perspectives. Despite being an area of low transmission risk, we found that the costs of treating MiP are not negligible. In particular, both from the patient and the provider perspectives, costs underwent a remarkable increase when admission was required and when the cost of subsequent P. vivax malaria episodes during the same pregnancy occurred. The information generated may help health policy decisions for the current control and future elimination of malaria in the area.

Malaria continues to represent a huge global health burden on the most vulnerable populations. The Intermittent Preventive Treatment (IPT) strategy has been shown to be an efficacious intervention in preventing most of the deleterious effects of malaria in pregnant women and infants. Yet, the effectiveness of the IPT strategy may be impaired by the increasing resistance to sulfadoxine-pyrimethamine (SP), and the scarcity of alternative antimalarial drugs.This review examines all the available information on IPT, in an aim to provide the scientific community with a framework to understand the benefits and limitations of this malaria control strategy. It includes the understanding of the historical background of the IPT strategy, the drug's mechanisms of actions, updated information on current available evidence, the implications of drug resistance and choice of alternative drugs, and a comprehensive discussion on the perspectives of IPT for malaria control in pregnant women and infants.IPT in pregnancy and infants is a cost-effective strategy that can contribute significantly to the control of malaria in endemic areas. Monitoring its effectiveness will allow tracking of progress, evaluation of the adequacy of currently used drugs and will highlight the eventual need for new therapies or alternative interventions.

Background. Accurate diagnosis of malaria infection during pregnancy remains challenging because of low parasite densities and placental sequestration of Plasmodium falciparum. The performance of different methods to detect P. falciparum in pregnancy and the clinical relevance of undetected infections were evaluated. Methods. P. falciparum infections were assessed in 272 Mozambican women at delivery by microscopy, placental histology, quantitative polymerase chain reaction (qPCR) and detection of histidine-rich protein 2 (HRP2) in plasma by enzyme-linked immunosorbent assay (ELISA) and a rapid diagnostic test (RDT). Association between infection and delivery outcomes was determined. Results. Among the 122 women qPCR-positive for P. falciparum in peripheral and/or placental blood samples, 87 (71.3%) did not receive a positive diagnosis by peripheral microscopy, 75 (61.5%) by HRP2 ELISA, and 74 (60.7%) by HRP2 RDT in plasma. Fifty-seven of the 98 qPCR-positive placental infections (58.2%) were not detected by histology. Women who were qPCR-positive but negative in their peripheral blood by microscopy or HRP2 RDT in plasma (n 5 62) were at increased risk of anemia, compared with negative women (n 5 141; odds ratio, 2.03; 95% confidence interval, 1.07‐3.83; P 5 .029). Conclusions. Microscopy, placental histology and HRP2-based plasma diagnostic methods fail to identify the majority of the P. falciparum infections detected by qPCR in peripheral and placental blood. Undetected infections were associated with maternal anemia, highlighting the urgent need for more accurate malaria diagnostic tools for pregnant women to avoid the negative clinical impact that hidden infections can have during pregnancy. Clinical Trials Registration. NCT00209781.

Introduction The collection of incidence data on HIV infection is necessary to evaluate the status and dynamics of the epidemic and the effectiveness of intervention strategies. However, this is usually difficult in low-income countries. Methods Five yearly point HIV prevalence estimations (in 1999, 2003, 2004, 2005 and 2008) were obtained for women between 15 and 45 years of age participating in three studies carried out for other purposes at the Antenatal Clinic (ANC) in Manhica, Mozambique. HIV incidence was estimated between prevalence points using a previously validated methodology. Two methods were used, one based on mortality rates for three HIV epidemic scenarios, and the other based on survival information after infection. The pattern over time was captured by fitting a log-regression model. Results The prevalence of HIV infection ranged from 12% in 1999 to 49% in 2008. The HIV incidence increased from approximately 3.5 cases per 100 person-years in 2001 to 14 per 100 person-years in 2004, with stabilization thereafter to levels of around 12 cases per 100 person-years. The incidence estimates were comparable for the two methods used. Conclusion These findings indicate an increase in the prevalence and incidence of HIV infection among women of reproductive age over the 9 years of the analysis, with a plateau in the incidence of infection since 2005. However, the very high figures for both prevalence and incidence highlight the importance of the continuation of the prevention and treatment programmes that already exist, and suggest that implementation of preventive measures is needed in this area.

Background. There is some consensus that malaria in pregnancy may negatively affect infant’s mortality and malaria morbidity, but there is less evidence concerning the factors involved. Methods. A total of 1030 Mozambican pregnant women were enrolled in a randomized, placebo-controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, and their infants were followed up throughout infancy. Overall mortality and malaria morbidity rates were recorded. The association of maternal and fetal risk factors with infant mortality and malaria morbidity was assessed. Results. There were 58 infant deaths among 997 live-born infants. The risk of dying during infancy was increased among infants born to women with acute placental infection (odds ratio [OR], 5.08 [95% confidence interval (CI), 1.77–14.53)], parasitemia in cord blood (OR, 19.31 [95% CI, 4.44–84.02]), low birth weight (OR, 2.82 [95% CI, 1.27–6.28]) or prematurity (OR, 3.19 [95% CI, 1.14–8.95]). Infants born to women who had clinical malaria during pregnancy (OR, 1.96 [95% CI, 1.13–3.41]) or acute placental infection (OR, 4.63 [95% CI, 2.10– 10.24]) had an increased risk of clinical malaria during infancy. Conclusions. Malaria infection at the end of pregnancy and maternal clinical malaria negatively impact survival and malaria morbidity in infancy. Effective clinical management and prevention of malaria in pregnancy may improve infant’s health and survival.

Pregnant women are susceptible to Plasmodium falciparum parasites that sequester in the placenta. The massive accumulation of infected erythrocytes in the placenta has been suggested to trigger the deleterious effects of malaria in pregnant women and their offspring. The risk of malaria is also high during the postpartum period, although mechanisms underlying this susceptibility are not known. Here, we aimed to identify host factors contributing to the risk of postpartum infections and to determine the origin of postpartum parasites by comparing their genotypes with those present at the time of delivery. To address this, blood samples were collected at delivery ( n = 402) and postpartum ( n = 354) from Mozambican women enrolled in a trial of intermittent preventive treatment in pregnancy (IPTp). P. falciparum was detected by real-time quantitative PCR (qPCR), and the parasite merozoite surface protein 1 ( msp-1 ) and msp-2 genes were genotyped. Fifty-seven out of 354 (16%) women were infected postpartum as assessed by qPCR, whereas prevalence by optical microscopy was only 4%. Risk of postpartum infection was lower in older women (odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.15 to 0.81) and higher in women with a placental infection at delivery (OR = 4.20, 95% CI = 2.19 to 8.08). Among 24 women with matched infections, 12 (50%) were infected postpartum with at least one parasite strain that was also present in their placentas. These results suggest that parasites infecting pregnant women persist after delivery and increase the risk of malaria during the postpartum period. Interventions that reduce malaria during pregnancy may translate into a lower risk of postpartum infection.

OBJECTIVES To describe the prevalence, aetiology and prognostic implications of coexisting invasive bacterial disease in children admitted with severe malaria in a rural Mozambican Hospital. METHODS Retrospective study of data systematically collected from June 2003 to May 2007 in a rural Mozambican hospital, from all children younger than 5 years admitted with severe malaria. RESULTS Seven thousand and forty-three children were admitted with a diagnosis of malaria. 25.2% fulfilled the criteria for severe malaria. 5.4% of the children with severe malaria and valid blood culture results had a concomitant bacteraemia. Case fatality rates of severe malaria cases rose steeply when bacteraemia was also present (from 4.0% to 22.0%, P < 0.0001), and bacteraemia was an independent risk factor for death among severe malaria patients (adjusted OR 6.2, 95% CI 2.8-13.7, P = 0.0001). Streptococcus pneumoniae, Gram-negative bacteria, Staphilococcus aureus and non-typhoid Salmonella (NTS) were the most frequently isolated microorganisms among severe malaria cases. Their frequency and associated case fatality rates (CFR) varied according to age and to syndromic presentation. Streptococcus pneumoniae had a relatively low CFR, but was consistently associated with severe malaria syndromes, or anaemia severity groups. No clear-cut relationship between malarial anaemia and NTS bacteraemia was found. CONCLUSIONS The coexistence of malaria and invasive bacterial infections is a frequent and life-threatening condition in many endemic African settings. In Mozambique, S. pneumoniae is the leading pathogen in this interaction, possibly as a consequence of the high HIV prevalence in the area. Measures directed at reducing the burden of both those infections are urgently needed to reduce child mortality in Africa.

Although community-acquired bacteremia is an important cause of childhood mortality in Africa, recognition of disease burden and potential impact of bacterial vaccines is limited.Blood cultures for bacterial pathogens were conducted systematically among children15 years of age admitted to Manhiça District Hospital, from 2001 to 2006.Blood-stream infections were identified in 8% (1550/19,896) of pediatric hospital admissions. Nontyphoidal Salmonella (NTS) and Pneumococcus were the most prevalent pathogens isolated (26% and 25% of 1550 cases, respectively). Until 28 days of life, Staphylococcus aureus (39%) and group B Streptococcus (20%) predominated. Incidence of community-acquired bacteremia per 100,000 child-years was 1730/10 in children1 year old, 782/10 in 1-4 year oldd, and 49/10 in children 5 years and older. Case-fatality of bacteremia was 12%. Community-acquired bacteremia associated mortality accounted for 21% (162/788) of hospital deaths. Resistance to antibiotics commonly used in Mozambique was high among invasive isolates of Haemophilus influenzae, Escherichia coli, and NTS.Community-acquired bacteremia is an important cause of pediatric hospital admission and death in rural African hospitals. The high burden of disease, mortality, and pattern of antibiotic resistance associated with bacteremia underscore the need for prevention in Sub-Saharan Africa.

In this study, we analyzed the human immunodeficiency type 1 (HIV-1) viruses circulating between 1999 and 2004 in antiretroviral-naive women from a rural area of southern Mozambique. Nucleotide sequencing of the HIV-1 long terminal repeat (LTR) U3, envelope (env) C2V3C3, and protease (pr) genomic regions was performed from women sera samples collected in 1999 and 2004. Phylogenetic analysis revealed that all amplified sequences belonged to subtype C. Although env sequences were predominantly CCR5-tropic (R5), CXCR4-tropic (X4) variants were also identified (13%). Both 1999 and 2004 sequences were widely dispersed across multiple clusters and were related to different reference sequences from neighboring countries. Sequences from 2004 showed significantly more nucleotide genetic diversity than sequences from 1999. Importantly, genetic diversification was also observed at the pr and env amino acid level, suggesting that positive selection forces were implicated in the viral diversification. These results indicate the rapid spread and diversification of subtype C virus in Mozambique where HIV-1 prevalence in the Manhiça antenatal clinic reached 23% in 2004.

Pregnancy triggers immunological changes aimed to tolerate the fetus. However, it has not been properly addressed whether similar changes occur in tropical areas with high infection pressure and whether these changes render women more susceptible to infectious diseases. We compared the frequencies of T cell subsets, including regulatory T cells, in pregnant and nonpregnant women from Papua New Guinea, a high malaria transmission area, and from Spain, a malaria-free country. We also assessed the relationship among these cellular subsets, malaria infection, and delivery outcomes. CD4+FOXP3+CD127low T cells (Tregs) were decreased in pregnant women in both countries but were not associated with malaria infection or poor delivery outcomes. An expansion of IFN-γ–producing cells and intracytoplasmic IFN-γ levels was found in pregnant compared with nonpregnant women only in Papua New Guinea. Increased CD4+IL-10+IFN-γ+ frequencies and Treg–IFN-γ production were found in women with current Plasmodium falciparum infection. Higher CD4+IL-10−IFN-γ+ T cells frequencies and production of proinflammatory cytokines (including TNF and IL-2) at recruitment (first antenatal visit) had a protective association with birth weight and future (delivery) P. falciparum infection, respectively. Higher intracellular IL-10 levels in T cells had a protective association with future P. falciparum infection and hemoglobin levels at delivery. The protective associations were found also with nonmalaria-specific T cell responses. Treg frequencies positively correlated with plasma eotaxin concentrations, but this subset did not express eotaxin receptor CCR3. Thus, an activated immune system during pregnancy might contribute to protection against malaria during pregnancy and poor delivery outcomes.

Migration has contributed to the emergence of certain infectious diseases in host countries. In Spain the number of immigrants has increased exponentially in recent decades. The aim of this review is to identify and analyze the available information on imported parasitic diseases in immigrant population in our country.A scope review of original articles published on imported parasitic diseases between 1998 and 2012. Study populations from Latin America, Africa, Asia, Eastern Europe and individuals who are under the definition of an immigrant from International Organization for Migration were included. The literature search was performed in the Medline and MEDES-MEDicina databases.A total of 51 descriptive studies were included in the analysis. Most immigrants attended at referral health facilities were originally from sub-Saharan Africa (between 16%-87%), followed by Latin America (13%-37%), while Asia was the region less represented (0.2%-8.8%). A considerable proportion (6.5-31%) of immigrants that attended to referral units of tropical medicine or inmigrant health, and that were originally from Latin America, particularly those from Bolivia, are affected by the Chagas disease, and several cases of mother-to-child transmission have been registered in our country.Imported parasitosis is a frequent diagnosis among migrant population. This review highlight the impact that migration has had on the emergence of certain imported parasitic diseases, being Chagas disease the most paradigmatic example.

Monitoring interventions to prevent malaria in pregnancy requires sensitive detection of placental infection. Rapid diagnostic tests (RDTs) are good candidates, but little information is available on their sensitivity on placental blood. We have evaluated the agreement (kappa coefficient) between microscopy and a Plasmodium falciparum histidine-rich protein 2 (HRP2)-based immuno-chromatographic test (ICT) on placental blood from 1151 women at delivery. Prevalences of placental infection by microscopy and RDT were 5.1% and 5.0%, respectively, showing 82.9% agreement (p0.0001). Discordances were found at low parasitemias (500 parasites/μL) or negative microscopy. The results suggest that the HRP2-RDTs from ICT diagnostics is a good alternative to microscopy for diagnosing placental malaria at delivery.

OBJECTIVES: To identify the determinants of institutional delivery among young married women in Nepal. DESIGN: Nepal Demographic and Health Survey (NDHS) data sets 2011 were analysed. Bivariate and multivariate logistic regression analyses were performed using a subset of 1662 ever-married young women (aged 15-24 years). OUTCOME MEASURE: Place of delivery. RESULTS: The rate of institutional delivery among young married women was 46%, which is higher than the national average (35%) among all women of reproductive age. Young women who had more than four antenatal care (ANC) visits were three times more likely to deliver in a health institution compared with women who had no antenatal care visit (OR: 3.05; 95% CI: 2.40 to 3.87). The probability of delivering in an institution was 69% higher among young urban women than among young women who lived in rural areas. Young women who had secondary or above secondary level education were 1.63 times more likely to choose institutional delivery than young women who had no formal education (OR: 1.626; 95% CI: 1.171 to 2.258). Lower use of a health institution for delivery was also observed among poor young women. Results showed that wealthy young women were 2.12 times more likely to deliver their child in an institution compared with poor young women (OR: 2.107; 95% CI: 1.53 to 2.898). Other factors such as the age of the young woman, religion, ethnicity, and ecological zone were also associated with institutional delivery. CONCLUSIONS: Maternal health programs should be designed to encourage young women to receive adequate ANC (at least four visits). Moreover, health programs should target poor, less educated, rural, young women who live in mountain regions, are of Janajati ethnicity and have at least one child as such women are less likely to choose institutional delivery in Nepal.