Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon.

BACKGROUND: Malaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed to Plasmodium (P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting from P. vivax infections remain poorly studied. As such, we aimed to evaluate the consequences of P. vivax infections during gestation on the health of mothers and their neonates in an endemic area of the Amazon. METHODS AND FINDINGS: We have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn's anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against the P. vivax (Pv) MSP119 protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed that P. vivax infections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69-24.54, p < 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29-9.97, p = 0.01). Histopathology analysis showed marked differences between placentas from P. vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP119 IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes. CONCLUSIONS: This study indicates that P. vivax malaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP119 are not protective against poor pregnancy outcomes induced by P. vivax infections

Association of Malaria Infection During Pregnancy With Head Circumference of Newborns in the Brazilian Amazon.

Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria

Association between gestational malaria, intrauterine growth restriction and low birth weight in the far-western Brazilian Amazon.

A malária é uma doença parasitária grave e quando ocorre durante a gravidez é uma das principais causas de mortalidade materno-infantil, podendo apresentar como consequências anemia materna, aborto, nascimento prematuro, restrição do crescimento intrauterino e baixo peso ao nascer (BPN). A infecção por Plasmodium (P.) falciparum é reconhecida como um determinante importante de consequências sérias durante a gravidez e efeitos adversos semelhantes também foram relatados em infecções por P. vivax. A despeito de sua alta prevalência e a sua possível associação com importantes complicações durante a gravidez, os efeitos da malária para gestantes e seus conceptos ainda não estão totalmente compreendidos. Este trabalho propõe estudar as consequências da malária gestacional e sua associação com a restrição do crescimento intrauterino e baixo peso ao nascer em uma área endêmica no extremo oeste da Amazônia brasileira. Foi realizado um estudo retrospectivo e prospectivo composto por gestantes da região do Vale do Alto Juruá (Acre, Brasil), no qual foram avaliadas as consequências e a extensão do efeito da malária sobre o recém-nascido através da coleta de dados epidemiológicos e material biológico. Neste estudo, foi observado um aumento no número de partos prematuros e BPN entre os recém-nascidos das gestantes infectadas por P. vivax quando comparadas com o grupo não infectado. Em relação à infecção por P. falciparum durante a gravidez, observamos que a doença representou um fator de risco para o nascimento de neonatos com perímetro cefálico reduzido, assim como uma maior probabilidade de ocorrência de casos de microcefalia e nascimentos prematuros. Além disso, todos esses efeitos adversos estavam ligados à malária placentária, caracterizada principalmente por um aumento de agregados nucleares sinciciais e infiltrados inflamatórios, bem como um forte desequilíbrio dos fatores angiogênicos e diminuição dos níveis de leptina. Muitos estudos, realizados principalmente na África, destacam os efeitos deletérios da malária por P. falciparum no contexto materno-fetal, mas pouco se sabe sobre a malária gestacional nas áreas endêmicas da América, onde predominam as infecções por P. vivax. Nossos resultados sugerem que infecções por esta espécie estão longe de serem benignas em razão da alta incidência de lesões placentárias, baixo peso ao nascer, abortos e partos prematuro em nossa casuística. Além disso, este estudo também mostrou que a malária gestacional por P. falciparum aumentou a probabilidade de partos prematuros e a ocorrência da redução do perímetro cefálico nos recém-nascidos, o que está associado à malária placentária. Assim, o conhecimento do impacto da infecção sobre a placenta e no desenvolvimento fetal poderá trazer uma importante contribuição para o entendimento da malária gestacional, além de possibilitar o desenvolvimento de ações específicas na rotina de cuidado pré-natal.Malaria is a severe parasitic disease that, when occurs during pregnancy, it is one of the main cause of maternal-fetal mortality leading also to maternal anemia, abortion, preterm birth, intrauterine growth restriction and low birth weight. Infections by Plasmodium (P.) falciparum are known to be detrimentally involved in poor pregnancy outcomes, effects that were also described during P. vivax infections. Despite its significant prevalence and possible association to severe complications during pregnancy, the impact of malaria in pregnant women and their children are not clearly understood. Current study aims to evaluate the consequences of malaria in pregnancy and correspondent association with intrauterine growth restriction and low birth weight in an endemic area located in the furthest west region of the Brazilian Amazon. A retrospective and prospective study was performed, accounting with pregnant women living in the region of Vale do Alto Juruá (Acre, Brazil) in which the consequences and extension of malaria effects on the newborns was evaluated through the analysis of epidemiological data and biological material. In this study, we observed an increase in the number of preterm deliveries and low birth weight among children born from pregnant women infected with P. vivax when compared to non-infected pregnant women. Regarding P. falciparum infection during pregnancy, we have noticed that this is a risk factor for newborns with reduced head circumference, also increasing the probability of occurring cases of microcephaly and preterm birth. Besides, every deleterious effect was associated with placental malaria, which is mainly characterized by an increase in the syncytial nuclear aggregates and inflammatory infiltrates, as well as by an imbalance in placental angiogenic factors and a reduction in leptin levels. Several studies mainly developed in Africa, highlight the negative effects of P. falciparum malaria in the maternal-fetal context yet, little is known about malaria in pregnancy that occurs in the endemic areas of the America where infections caused by P. vivax are predominate. Our results suggest that infections promoted by this parasite species are far from being benign as it was depicted in our cohort, which has shown high incidence of placental lesions, low birth weight, abortion and preterm delivery. Moreover, the present study has shown that malaria in pregnancy caused by P. falciparum increased the probability of preterm delivery and reduction of head circumference in newborns, which is associated to placental malaria. Therefore, knowing the impact of infection in the placenta and fetal development may bring an important contribution to the understanding of malaria in pregnancy, allowing the development of specific action that can be implemented in the routine of antenatal cares

Atuação do enfermeiro na prescrição de contraceptivos hormonais na rede de atenção primária em saúde

O estudo teve como objetivo conhecer e analisar a atuação do enfermeiro na prescrição dos contraceptivos hormonais reversíveis na Rede de Atenção Primária a Saúde. Trata-se de um estudo transversal e descritivo, tendo como sujeitos 64 enfermeiros lotados nas unidades assistenciais no período de setembro a novembro de 2010 no município de Rio Branco-Acre. Os dados foram coletados mediante entrevistas estruturadas utilizando um questionário. Os resultados evidenciaram que 96,9% dos enfermeiros prescrevem os métodos anticoncepcionais e que 90,6% tem conhecimento da legislação que rege a prescrição de enfermagem. Foi observado que a escolha do método contraceptivo pelos enfermeiros baseia-se na escolha da cliente e anamnese (36% e 34% respectivamente), e que 90% sempre orientavam quanto às vantagens e desvantagens de cada método. Assim, para escolher um método contraceptivo de forma livre e informada, os métodos devem estar disponíveis e devem ser dispensados por profissionais capacitados, após orientação correta e completa

Genetic diversity of Plasmodium vivax isolates from pregnant women in the Western Brazilian Amazon: a prospective cohort study

BACKGROUND: Each year, 92 million pregnant women are at risk of contracting malaria during pregnancy, with the underestimation of the mortality and morbidity burden associated with Plasmodium vivax. During pregnancy, P. vivax infection is associated with low birth weight, maternal anaemia, premature delivery, and stillbirth. In the State of Acre (Brazil), high transmission leaves pregnant women at greater risk of contracting malaria and having a greater number of recurrences. The study of genetic diversity and the association of haplotypes with adverse pregnancy effects is of great importance for the control of the disease. Here we investigate the genetic diversity of P. vivax parasites infecting pregnant women across their pregnancies. METHODS: P. vivax DNA was extracted from 330 samples from 177 women followed during pregnancy, collected in the State of Acre, Brazil. All samples were negative for Plasmodium falciparum DNA. Sequence data for the Pvmsp1 gene was analysed alongside data from six microsatellite (MS) markers. Allelic frequencies, haplotype frequencies, expected heterozygosity (HE) were calculated. Whole genome sequencing (WGS) was conducted on four samples from pregnant women and phylogenetic analysis performed with other samples from South American regions. FINDINGS: Initially, the pregnant women were stratified into two groups-1 recurrence and 2 or more recurrences-in which no differences were observed in clinical gestational outcomes or in placental histological changes between the two groups. Then we evaluated the parasites genetically. An average of 18.5 distinct alleles were found at each of the MS loci, and the HE calculated for each marker indicates a high genetic diversity occurring within the population. There was a high percentage of polyclonal infections (61.7%, 108/175), and one haplotype (H1) occurred frequently (20%), with only 9 of the haplotypes appearing in more than one patient. INTERPRETATION: Most pregnant women had polyclonal infections that could be the result of relapses and/or re-infections. The high percentage of H1 parasites, along with the low frequency of many other haplotypes are suggestive of a clonal expansion. Phylogenetic analysis shows that P. vivax population within pregnant women clustered with other Brazilian samples in the region. FUNDING: FAPESP and CNPq - Brazil

Plasmodium falciparum infection dysregulates placental autophagy.

Plasmodium (P.) falciparum malaria during pregnancy has been frequently associated with severe consequences such as maternal anemia, abortion, premature birth, and reduced birth weight. Placental damage promotes disruption of the local homeostasis; though, the mechanisms underlying these events are still to be elucidated. Autophagy is a fundamental homeostatic mechanism in the natural course of pregnancy by which cells self-recycle in order to survive in stressful environments. Placentas from non-infected and P. falciparum-infected women during pregnancy were selected from a previous prospective cohort study conducted in the Brazilian Amazon (Acre, Brazil). Newborns from infected women experienced reduced birth weight (P = 0.0098) and placental immunopathology markers such as monocyte infiltrate (P < 0.0001) and IL-10 production (P = 0.0122). The placentas were evaluated for autophagy-related molecules. As a result, we observed reduced mRNA levels of ULK1 (P = 0.0255), BECN1 (P = 0.0019), and MAP1LC3B (P = 0.0086) genes in placentas from P. falciparum-infected, which was more striking in those diagnosed with placental malaria. Despite the protein levels of these genes followed the same pattern, the observed reduction was not statistically significant in placentas from P. falciparum-infected women. Nevertheless, our data suggest that chronic placental immunopathology due to P. falciparum infection leads to autophagy dysregulation, which might impair local homeostasis during malaria in pregnancy that may result in poor pregnancy outcomes

Time-series of gestational malaria cases between 2006–2014.

<p>(A) Number of gestational malaria cases per species, (B) mean birth weight of newborns from non-infected and infected women during pregnancy.</p

Baseline characteristics of mothers at delivery.

<p>Baseline characteristics of mothers at delivery.</p