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      Maternal, placental and cord blood cytokines and the risk of adverse birth outcomes among pregnant women infected with Schistosoma japonicum in the Philippines

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          Abstract

          Background

          The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment.

          Methods/Findings

          This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12–16 weeks’ gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks’ gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated.

          Conclusions

          Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface.

          Clinical Trial Registry number and website

          ClinicalTrials.gov ( NCT00486863).

          Author summary

          Schistosomiasis is one of the most prevalent parasitic tropical diseases, and it is primarily treated with the drug praziquantel. This study examined the effects of praziquantel treatment for schistosomiasis and the presence of geohelminth infections during pregnancy on cytokines in maternal, placental, and cord blood, and examined the effects of pro-inflammatory signatures at the maternal-fetal interface on perinatal outcomes. We analyzed the data of 369 mother-infant pairs obtained from a randomized controlled trial of praziquantel given at 12–16 weeks’ gestation. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Elevated levels of both Th1 and Th2 cytokines were associated with the risk of adverse perinatal outcomes (small-for-gestational age and prematurity). Hookworm coinfection at 12 weeks’ gestation was, however, related to elevated levels of certain cytokines in the placenta (IL-1, IL-5, CXCL8 and IFN-γ).

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          Most cited references40

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          Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis.

          Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain. To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens. ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy. Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models. Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events. Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.
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            Best (but oft-forgotten) practices: the multiple problems of multiplicity-whether and how to correct for many statistical tests.

            Testing many null hypotheses in a single study results in an increased probability of detecting a significant finding just by chance (the problem of multiplicity). Debates have raged over many years with regard to whether to correct for multiplicity and, if so, how it should be done. This article first discusses how multiple tests lead to an inflation of the α level, then explores the following different contexts in which multiplicity arises: testing for baseline differences in various types of studies, having >1 outcome variable, conducting statistical tests that produce >1 P value, taking multiple "peeks" at the data, and unplanned, post hoc analyses (i.e., "data dredging," "fishing expeditions," or "P-hacking"). It then discusses some of the methods that have been proposed for correcting for multiplicity, including single-step procedures (e.g., Bonferroni); multistep procedures, such as those of Holm, Hochberg, and Šidák; false discovery rate control; and resampling approaches. Note that these various approaches describe different aspects and are not necessarily mutually exclusive. For example, resampling methods could be used to control the false discovery rate or the family-wise error rate (as defined later in this article). However, the use of one of these approaches presupposes that we should correct for multiplicity, which is not universally accepted, and the article presents the arguments for and against such "correction." The final section brings together these threads and presents suggestions with regard to when it makes sense to apply the corrections and how to do so.
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              The Th1:Th2 Dichotomy of Pregnancy and Preterm Labour

              Pregnancy is a unique immunological state in which a balance of immune tolerance and suppression is needed to protect the fetus without compromising the mother. It has long been established that a bias from the T helper 1 cytokine profile towards the T helper 2 profile contributes towards successful pregnancy maintenance. The majority of publications that report on aberrant Th1:Th2 balance focus on early pregnancy loss and preeclampsia. Over the last few decades, there has been an increased awareness of the role of infection and inflammation in preterm labour, and the search for new biomarkers to predict preterm labour continues. In this paper, we explore the evidence for an aberrant Th1:Th2 profile associated with preterm labour. We also consider the potential for its use in screening women at high risk of preterm labour and for prophylactic therapeutic measures for the prevention of preterm labour and associated neonatal adverse outcomes.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                12 June 2019
                June 2019
                : 13
                : 6
                : e0007371
                Affiliations
                [1 ] Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, United States of America
                [2 ] Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, RI, United States of America
                [3 ] Graduate School of Urban Public Health, University of Seoul, Seoul, Republic of Korea
                [4 ] Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States of America
                [5 ] Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, RI, United States of America
                [6 ] Departments of Clinical Immunology and Transfusion Medicine, Linkoping University, Linkoping, Sweden
                [7 ] Departments of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
                [8 ] Remedios Trinidad Romualdez Hospital, Tacloban City, Leyte, The Philippines
                [9 ] Research Institute for Tropical Medicine, Manila, Philippines
                University of Cambridge, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-2407-0962
                http://orcid.org/0000-0001-9456-2044
                Article
                PNTD-D-18-00572
                10.1371/journal.pntd.0007371
                6590831
                31188820
                382f916d-8548-46f4-b0a8-bb05baf91a2b
                © 2019 Abioye et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 April 2018
                : 8 April 2019
                Page count
                Figures: 5, Tables: 4, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: U01AI066050
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R21AI107520
                Award Recipient :
                1) The randomized controlled trial was supported by NIH/NIAID, “ S. japonicum and pregnancy outcomes: An RCT” (U01AI066050) with relevant data for this manuscript collected through newborn day of life 28. 2) NIH/NIAID (R21AI107520), “ S. japonicum, anemia, and iron transport in human pregnancy” supported extended biomarkers to define etiology of anemia among pregnant women and their offspring. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
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                Innate Immune System
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                Medicine and Health Sciences
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                Trichuriasis
                Medicine and Health Sciences
                Parasitic Diseases
                Helminth Infections
                Schistosomiasis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Schistosomiasis
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-06-24
                Qualified researchers can inquire about the data by contacting Archie Pablo ( pablo1128@ 123456yahoo.com ).

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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