Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy

Importance of the field: Malaria infection during pregnancy is a major public health problem worldwide, with 50 million pregnancies exposed to the infec- tion every year. Approximately 25,000 maternal deaths and between 75,000 and 200,000 infant deaths could be prevented each year by effective malaria control in pregnancy. Antimalarial drug treatment and prevention has been hampered by the appearance of drug resistance, which has been a particular problem in pregnancy due to the inherent safety issues. Areas covered in this review: New antimalarial drugs and combinations are being studied but there is not yet sufficient information on their efficacy or, more importantly, on their safety in pregnancy. This article provides an over- view of the relevance of the topic and reviews the current antimalarial drugs recommended for pregnancy, as well as the guidelines for both treatment and prevention in women living in endemic areas and for travellers. What the reader will gain: Updated information on the drugs currently used for malaria treatment and prevention in pregnancy, including new drugs under development, is provided. The gaps on efficacy and safety information for use during pregnancy are also discussed. Take home message: Prevention and case management of malaria during pregnancy is based on risk--benefit criteria and poses one of the greatest challenges to current malaria control.Importância do campo: a infecção por malária durante a gravidez é um grande público problema de saúde em todo o mundo, com 50 milhões de gestações expostas à infecção ção todos os anos. Aproximadamente 25.000 mortes maternas e entre 75.000 e 200.000 mortes infantis poderiam ser evitadas a cada ano por malária eficaz controle na gravidez. O tratamento e a prevenção com medicamentos antimaláricos tem sido dificultado pelo aparecimento de resistência aos medicamentos, que tem sido um particular problema na gravidez devido aos problemas de segurança inerentes. Áreas abrangidas nesta revisão: Novos medicamentos antimaláricos e combinações são em estudo, mas ainda não há informações suficientes sobre sua eficácia ou, mais importante, sobre sua segurança durante a gravidez. Este artigo fornece uma visão geral visão da relevância do tema e analisa os medicamentos antimaláricos atuais recomendado para gravidez, bem como as orientações para ambos os tratamentos e prevenção em mulheres que vivem em áreas endêmicas e para viajantes. O que o leitor vai ganhar: informações atualizadas sobre os medicamentos usados ​​atualmente para tratamento e prevenção da malária na gravidez, incluindo novos medicamentos em desenvolvimento, é fornecido. As lacunas nas informações de eficácia e segurança para uso durante a gravidez também são discutidos. Mensagem para levar para casa: Prevenção e gestão de casos de malária durante a gravidez é baseada em critérios de risco - benefício e representa um dos maiores desafios ao controle atual da malária.(TRADUÇÃO NOSSA

A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected

Raquel Gonzalez and colleagues highlight an urgent need to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis

Obstetric fistulae in southern Mozambique: incidence, obstetric characteristics and treatment.

BACKGROUND: Obstetric fistula is one of the most devastating consequences of unmet needs in obstetric services. Systematic reviews suggest that the pooled incidence of fistulae in community-based studies is 0.09 per 1000 recently pregnant women; however, as facility delivery is increasing, for the most part, in Africa, incidence of fistula should decrease. Few population-based studies on fistulae have been undertaken in Sub-Saharan Africa, including Mozambique. This study aimed to estimate the incidence of obstetric fistulae in recently delivered mothers, and to describe the clinical characteristics and care, as well as the outcome, after surgical repair. METHODS: We selected women who had delivered up to 12 months before the start of the study (June, 1st 2016). They were part of a cohort of women of reproductive age (12-49 years), recruited from selected clusters in rural areas of Maputo and Gaza provinces, Southern Mozambique, who were participating in an intervention trial (the Community Level Interventions for Pre-eclampsia trial or CLIP trial). Case identification was completed by self-reported constant urine leakage and was confirmed by clinical assessment. Women who had confirmed obstetric fistulae were referred for surgical repair. Data were entered into a REDCap database and analysed using R software. RESULTS: Five women with obstetric fistulae were detected among 4358 interviewed, giving an incidence of 1.1 per 1000 recently pregnant women (95% CI 2.16-0.14). All but one had Caesarean section and all of the babies died. Four were stillborn, and one died very soon after birth. All of the patients identified and reached the primary health facility in reasonable time. Delays occurred in the care: in diagnosis of obstructed labour, and in the decision to refer to the secondary or third-level hospital. All but one of the women were referred to surgical repair and the fistulae successfully closed. CONCLUSION: This population-based study reports a high incidence of obstetric fistulae in an area with high numbers of facility births. Few first and second delays in reaching care, but many third delays in receiving care, were identified. This raises concerns for quality of care

Clinical malaria in African pregnant women

<p>Abstract</p> <p>Background</p> <p>There is a widespread notion, based on limited information, that in areas of stable malaria transmission most pregnant women with <it>Plasmodium falciparum </it>infection are asymptomatic. This study aim to characterize the clinical presentation of malaria in African pregnant women and to evaluate the adequacy of case management based on clinical complaints.</p> <p>Methods</p> <p>A hospital-based descriptive study between August 2003 and November 2005 was conducted at the maternity clinic of a rural hospital in Mozambique. All women attending the maternity clinic were invited to participate. A total of 2,330 women made 3,437 eligible visits, 3129 were analysed, the remainder were excluded because diagnostic results were unavailable or they were repeat visits. Women gave a standardized clinical history and had a medical exam. Malaria parasitaemia and haematocrit in capillary blood was determined for all women with signs or symptoms compatible with malaria including: presence and history of fever, arthromyalgias, headache, history of convulsions and pallor. Outcome measure was association of malaria symptoms or signs with positive blood slide for malaria parasitaemia.</p> <p>Results</p> <p>In 77.4% of visits pregnant women had symptoms suggestive of malaria; 23% (708/3129) were in the first trimester. Malaria parasitaemia was confirmed in 26.9% (842/3129) of visits. Headache, arthromyalgias and history of fever were the most common symptoms (86.5%, 74.8% and 65.4%) presented, but their positive predictive values for malaria parasitaemia were low [28% (27–30), 29% (28–31), and 33% (31–35), respectively].</p> <p>Conclusion</p> <p>Symptoms suggestive of malaria were very frequent among pregnant women attending a rural maternity clinic in an area of stable malaria transmission. However, less than a third of them were parasitaemic. In the absence of microscopy or rapid diagnostic tests, a large proportion of women, including those in the first trimester of gestation, would be unnecessarily receiving antimalarial drugs, often those with unknown safety profiles for pregnancy. Accessibility to malaria diagnostic tools needs to be improved for pregnant women and drugs with a safety profile in all gestational ages are urgently needed.</p

Blood pressure thresholds in pregnancy for identifying maternal and infant risk: A secondary analysis of community-level interventions for pre-eclampsia (CLIP) trial data

Background: Blood pressure measurement is a marker of antenatal care quality. In well resourced settings, lower blood pressure cutoffs for hypertension are associated with adverse pregnancy outcomes. We aimed to study the associations between blood pressure thresholds and adverse outcomes and the diagnostic test properties of these blood pressure cutoffs in low-resource settings.Methods: We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials (NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10). We included pregnant women aged 15-49 years (12-49 years in Mozambique), identified in their community by trained community health workers, who had data on blood pressure measurements and outcomes. The trial was unmasked. Maximum blood pressure was categorised as: normal blood pressure (systolic blood pressure [sBP] [dBP] Hg), elevated blood pressure (sBP 120-129 mm Hg and dBP Hg), stage 1 hypertension (sBP 130-139 mm Hg or dBP 80-89 mm Hg, or both), non-severe stage 2 hypertension (sBP 140-159 mm Hg or dBP 90-109 mm Hg, or both), or severe stage 2 hypertension (sBP ≥160 mm Hg or dBP ≥110 mm Hg, or both). We classified women according to the maximum blood pressure category reached across all visits for the primary analyses. The primary outcome was a maternal, fetal, or neonatal mortality or morbidity composite. We estimated dose-response relationships between blood pressure category and adverse outcomes, as well as diagnostic test properties.Findings: Between Nov 1, 2014, and Feb 28, 2017, 21 069 women (6067 in India, 4163 in Mozambique, and 10 839 in Pakistan) contributed 103 679 blood pressure measurements across the three CLIP trials. Only women with non-severe or severe stage 2 hypertension, as discrete diagnostic categories, experienced more adverse outcomes than women with normal blood pressure (risk ratios 1·29-5·88). Using blood pressure categories as diagnostic thresholds (women with blood pressure within the category or any higher category vs those with blood pressure in any lower category), dose-response relationships were observed between increasing thresholds and adverse outcomes, but likelihood ratios were informative only for severe stage 2 hypertension and maternal CNS events (likelihood ratio 6·36 [95% CI 3·65-11·07]) and perinatal death (5·07 [3·64-7·07]), particularly stillbirth (8·53 [5·63-12·92]).Interpretation: In low-resource settings, neither elevated blood pressure nor stage 1 hypertension were associated with maternal, fetal, or neonatal mortality or morbidity adverse composite outcomes. Only the threshold for severe stage 2 hypertension met diagnostic test performance standards. Current diagnostic thresholds for hypertension in pregnancy should be retained.Funding: University of British Columbia, the Bill & Melinda Gates Foundation

Awareness of cervical cancer and willingness to be vaccinated against human papillomavirus in Mozambican adolescent girls

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 1,147 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 programs are critical for acceptance of new tools, and are encouraging for the reduction of cervical cancer related mortality and morbidity in Mozambique

Nevirapine hair and plasma concentrations and HIV-1 viral suppression among HIV infected ante-partum and post-partum women attended in a mother and child prevention program in Maputo city, Mozambique

Introduction: Prevention of mother to child transmission of HIV (PMTCT) is frequently challenged by irregular access to more effective anti-retroviral therapy. Nevirapine single dose (sdNVP), sdNVP+AZT+3TC for MTCT prophylaxis and NVP+ AZT+3TC for treatment and PMTCT were withdrawn due to low genetic resistance barrier and low efficacy. However current PMTCT lines in Mozambique include DTG+3TC+TDF, TDF+3TC+EFV, DTG +ABC+3TC, and AZT + NVP syrup prophylaxis for exposed babies. We assessed NVP hair and plasma concentrations and association with HIV-1RNA suppression among HIV+ ante-partum and post-partum women under PMTCT in Maputo, Mozambique. Methods: From December 2013 to November 2014, prospectively were enrolled 200 HIV+ ante-partum women on 200mg nevirapine and zidovudine 300 plus lamivudine 150mg twice daily at least with 3 months treatment and seen again at 24 weeks post-partum. Self-reported pill-taking adherence, NVP concentrations in hair, plasma, hemoglobin, CD4 cell count, HIV-1 RNA load was evaluated. NVP concentration in hair and plasma was analyzed as categorical quartile variable based on better data fit. NVP concentration was set between ≤3.77 ng/ml in plasma and ≤17,20 ng/mg in hair in quartile one to ≥5.36 ng/ml in plasma and ≥53.21 ng/mg in hair in quartile four. Logistic regression models for repeated measures were calculated. Following the World Health Organization (WHO) guidelines we set viral suppression at HIV-1RNA \u3c 1000 c/mL. Outcome was HIV-1 RNA\u3c1000 copies/ml. Predictor was NVP concentration in hair categorized in quartiles. Results: In total 369 person-visits (median of 1.85) were recorded. Self-reported adherence was 98% (IQR 97–100%) at ante-partum. In 25% person visits, NVP concentrations were within therapeutic levels (3.77 ng/ml to 5.35 ng/ml) in plasma and (17.20 ng/mg to 53.20 ng/mg) in hair. In 50% person visits NVP concentrations were above 5.36 ng/ml in plasm and 53.21 ng/mg in hair. HIV-1 RNA suppression was found in 34.7% of women with two viral loads, one at enrollment and another in post-partum. Odds of HIV-1 RNA suppression in quartile 4, was about 6 times higher than in quartile 1 (p-value = 0.006) for NVP hair concentration and 7 times for NVP plasma concentration (p-value = 0.012). Conclusions: The study results alert for potential low efficacy of current PMTCT drug regimens in use in Mozambique. Affordable means for individual monitoring adherence, ART plasma and hair levels, drug resistant and HIV-1 RNA levels monitoring are recommended for prompt identification of inadequate drug regimens exposure patterns and adjust accordingly

Maternal HIV infection is an important health determinant in non-HIV-infected infants

OBJECTIVE: To assess morbidity and mortality in HIV-exposed uninfected (HEU) children to help guiding appropriate clinical care and effective preventive interventions. DESIGN: This is a longitudinal study comparing two cohorts of children; one born to HIV-infected women and the other born to HIV-uninfected women. METHODS: We have analyzed prospectively obtained information on nutritional status, morbidity and mortality from 966 HEU and 909 HIV-unexposed infants followed up until their first 18 months of life at a referral health facility in southern Mozambique. Determinants for adverse health outcomes in HEU children were also assessed using multivariate logistic regression. RESULTS: Increased incidence of hospital admissions (P = 0.0015), shorter survival in the first 18 months of life (P = 0.0510) and moderate and severe malnutrition (P = 0.0006 and 0.0014, respectively) were observed among HEU children compared with HIV-unexposed children. Incidence of outpatient attendance in HEU children was associated with being men, older age and the mother being on antiretroviral treatment. Among HEU children, those who were never breastfed, or who were weaned or were partially breastfed, had an increased incidence of hospital admissions compared with children who were exclusively breastfed. CONCLUSION: Maternal HIV infection has important health consequences in non-HIV-infected children. As the prevalence of HIV-infected pregnant women is maintained and the proportion of HIV-infected children declines because of the scale-up of antiretroviral treatment during pregnancy and breastfeeding, more focus should be given to the health needs of HEU children to ensure that the post-2015 sustainable development goals are met

Ready to deliver maternal and newborn care? Health providers' perceptions of their work context in rural Mozambique.

BACKGROUND: Deficiencies in the provision of evidence-based obstetric care are common in low-income countries, including Mozambique. Constraints relate to lack of human and financial resources and weak health systems, however limited resources alone do not explain the variance. Understanding the healthcare context ahead of implementing new interventions can inform the choice of strategies to achieve a successful implementation. The Context Assessment for Community Health (COACH) tool was developed to assess modifiable aspects of the healthcare context that theoretically influence the implementation of evidence. OBJECTIVES: To investigate the comprehensibility and the internal reliability of COACH and its use to describe the healthcare context as perceived by health providers involved in maternal care in Mozambique. METHODS: A response process evaluation was completed with six purposively selected health providers to uncover difficulties in understanding the tool. Internal reliability was tested using Cronbach's α. Subsequently, a cross-sectional survey using COACH, which contains 49 items assessing eight dimensions, was administered to 175 health providers in 38 health facilities within six districts in Mozambique. RESULTS: The content of COACH was clear and most items were understood. All dimensions were near to or exceeded the commonly accepted standard for satisfactory internal reliability (0.70). Analysis of the survey data indicated that items on all dimensions were rated highly, revealing positive perception of context. Significant differences between districts were found for the Work culture, Leadership, and Informal payment dimensions. Responses to many items had low variance and were left-skewed. CONCLUSIONS: COACH was comprehensible and demonstrated good reliability, although biases may have influenced participants' responses. The study suggests that COACH has the potential to evaluate the healthcare context to identify shortcomings and enable the tailoring of strategies ahead of implementation. Supplementing the tool with qualitative approaches will provide an in-depth understanding of the healthcare context

Effects of HIV infection on maternal and neonatal health in southern Mozambique: A prospective cohort study after a decade of antiretroviral drugs roll out

INTRODUCTION: The HIV epidemic is concentrated in sub-Saharan Africa. However, limited information exists on its impact on women and infant's health since the introduction of antiretroviral drugs in this region, where health resources are often scarce. METHODS: The effect of HIV infection on maternal health, birth outcomes and infant health was analysed in two contemporary cohorts of HIV-uninfected and HIV-infected pregnant women from southern Mozambique. Pregnant women attending the first antenatal care visit were followed until one month after delivery. Antiretroviral therapy was administered based on CD4+T cell count and clinical stage. Maternal and neonatal morbidity and mortality, as well as pregnancy outcomes were assessed by mother's HIV status. RESULTS: A total of 1183 HIV-uninfected and 561 HIV-infected pregnant women were enrolled. HIV-infected women were more likely to have anaemia both at the first antenatal care visit and at delivery than HIV-uninfected women (71.5% versus 54.8% and 49.4% versus 40.6%, respectively, p<0.001). Incidence of hospital admissions during pregnancy was increased among HIV-infected women (RR, 2.04, [95%CI, 1.45; 2.86]; p<0.001). At delivery, 21% of HIV-infected women reported being on antiretroviral therapy, and 70% having received antiretroviral drugs for prevention of mother to child transmission of HIV. The risk of stillbirths was doubled in HIV-infected women (RR, 2.16 [95%CI 1.17; 3.96], p = 0.013). Foetal anaemia was also increased among infants born to HIV-infected women (10.6% versus 7.3%, p = 0.022). No differences were found in mean birth weight, malaria, prematurity and maternal and neonatal deaths between groups. CONCLUSIONS: HIV infection continues to be associated with significant maternal morbidity and poor neonatal health outcomes. Efforts should urgently be made to identify the barriers that impede improvements on the devastating effects of HIV in African women and their infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00811421