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      Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes

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          Abstract

          Background

          Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes.

          Methods

          This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12–20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants.

          Results

          The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0–1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (≥ 2 episodes of symptomatic malaria or ≥ 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80–111.6) and 4.06 (1.73–9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32–8.12) and aRR = 7.07 (2.84–17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46–21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy.

          Conclusion

          Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes.

          Trial Registration Current Controlled Trials Identifier NCT02163447

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12936-017-2040-4) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          Malaria in pregnancy: pathogenesis and immunity.

          Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta, and that dissect the relation between timing of infection and outcome, could allow improved targeting of preventive treatments and development of a vaccine for use in pregnant women.
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            The burden of malaria in pregnancy in malaria-endemic areas.

            Pregnant women in malarious areas may experience a variety of adverse consequences from malaria infection including maternal anemia, placental accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine growth retardation (IUGR), fetal parasite exposure and congenital infection, and infant mortality (IM) linked to preterm-LBW and IUGR-LBW. We reviewed studies between 1985 and 2000 and summarized the malaria population attributable risk (PAR) that accounts for both the prevalence of the risk factors in the population and the magnitude of the associated risk for anemia, LBW, and IM. Consequences from anemia and human immunodeficiency virus infection in these studies were also considered. Population attributable risks were substantial: malaria was associated with anemia (PAR range = 3-15%), LBW (8-14%), preterm-LBW (8-36%), IUGR-LBW (13-70%), and IM (3-8%). Human immunodeficiency virus was associated with anemia (PAR range = 12-14%), LBW (11-38%), and direct transmission in 20-40% of newborns, with direct mortality consequences. Maternal anemia was associated with LBW (PAR range = 7-18%), and fetal anemia was associated with increased IM (PAR not available). We estimate that each year 75,000 to 200,000 infant deaths are associated with malaria infection in pregnancy. The failure to apply known effective antimalarial interventions through antenatal programs continues to contribute substantially to infant deaths globally.
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              The impact of placental malaria on gestational age and birth weight.

              Maternal malaria is associated with reduced birth weight, which is thought to be effected through placental insufficiency, which leads to intrauterine growth retardation (IUGR). The impact of malaria on preterm delivery is unclear. The effects of placental malaria-related changes on birth weight and gestational age were studied in 1177 mothers (and their newborns) from Tanzania. Evidence of malaria infection was found in 75.5% of placental samples. Only massive mononuclear intervillous inflammatory infiltration (MMI) was associated with increased risk of low birth weight (odds ratio ¿OR, 4.0). Maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of premature delivery (OR, 3.2; OR, 2.1, respectively). MMI is an important mechanism in the pathogenesis of IUGR in malaria-infected placentas. This study also shows that placental malaria causes prematurity even in high-transmission areas. The impact of maternal malaria on infant mortality may be greater than was thought previously.
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                Author and article information

                Contributors
                kapisij@gmail.com
                abelkakuru@gmail.com
                prasj@stanford.edu
                marymkakuru@gmail.com
                paul.natureeba@gmail.com
                patriciaawori@yahoo.com
                ivuds@yahoo.com
                sekirchrd@yahoo.com
                polwoch@idrc-uganda.org
                ategekajohnnie@yahoo.com
                pnayebare@ymail.com
                Tamara.Clark@ucsf.edu
                Gabrielle.Rizzuto@ucsf.edu
                vkd6@cdc.gov
                diane.havlir@ucsf.edu
                mkamya@infocom.co.ug
                grant.dorsey@ucsf.edu
                stephanie.valderramos@ucsf.edu
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                5 October 2017
                5 October 2017
                2017
                : 16
                : 400
                Affiliations
                [1 ]ISNI 0000 0004 0620 0548, GRID grid.11194.3c, School of Medicine, , Makerere University College of Health Sciences, ; Kampala, Uganda
                [2 ]GRID grid.463352.5, Infectious Diseases Research Collaboration, ; Kampala, Uganda
                [3 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Medicine, , University of California, ; San Francisco, CA USA
                [4 ]ISNI 0000 0004 0620 0548, GRID grid.11194.3c, Department of Obstetrics and Gynecology, , Makerere University College of Health Sciences, ; Kampala, Uganda
                [5 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Pathology, , University of California, ; San Francisco, CA USA
                [6 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, Division of High-Consequence Pathogens and Pathology, , Centers for Disease Control and Prevention, ; Atlanta, GA USA
                [7 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, , University of California, ; San Francisco, CA USA
                [8 ]ISNI 0000000419368956, GRID grid.168010.e, Division of Infectious Diseases and Geographical Medicine, , Stanford University, ; Stanford, CA USA
                Article
                2040
                10.1186/s12936-017-2040-4
                5629777
                28982374
                fa810f8e-8175-42b9-bdcd-8edd7e1c07de
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 June 2017
                : 21 September 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;
                Award ID: P01HD059454
                Award Recipient :
                Funded by: Reproductive Scientist Development Programme
                Award ID: K12HD000849-26 (SLG)
                Award Recipient :
                Funded by: Burroughs Wellcome Fund as part of the Reproductive Scientist Development Programme
                Award ID: K12HD000849-26 (SLG)
                Award Recipient :
                Funded by: NIH Fogarty International Center
                Award ID: TW007375
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Infectious disease & Microbiology
                malaria,pregnancy,placental malaria,birth outcomes,asymptomatic parasitaemia,iptp,low birth weight,small for gestational age,preterm birth,lamp

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