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      Leptospirosis in pregnancy: A systematic review

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          Abstract

          Introduction

          Leptospirosis is a leading zoonotic disease worldwide with more than 1 million cases in the general population per year. With leptospirosis being an emerging infectious disease and as the world’s environment changes with more floods and environmental disasters, the burden of leptospirosis is expected to increase. The objectives of the systematic review were to explore how leptospirosis affects pregnancy, its burden in this population, its effects on maternal and fetal outcomes and the evidence base surrounding treatment options.

          Methods

          We performed a systematic review of published and unpublished literature using automated and manual methods to screen nine electronic databases since inception, with no language restriction. Two reviewers independently screened articles, completed the data extraction and assessment of risk of bias. Due to significant heterogeneity and paucity of data, we were unable to carry out a meta-analysis, but we conducted a pooled analysis of individual patient data from the case reports and case series to examine the patient and disease characteristics, diagnostic methods, differential diagnoses, antibiotic treatments, and outcomes of leptospirosis in pregnancy. The protocol for this review was registered on the International Prospective Register of Systematic Reviews, PROSPERO: CRD42020151501.

          Results

          We identified 419 records, of which we included eight observational studies, 21 case reports, three case series and identified four relevant ongoing studies. Overall the studies were with moderate bias and of ‘fair’ quality. We estimated the incidence of leptospirosis in pregnancy to be 1.3 per 10,000 in women presenting with fever or with jaundice, but this is likely to be higher in endemic areas. Adverse fetal outcomes were found to be more common in pregnant patients who presented in the second trimester compared with patients who presented in the third trimester. There is overlap between how leptospirosis presents in pregnancy and in the general population. There is also overlap between the signs, symptoms and biochemical disturbances associated with leptospirosis in pregnancy and the presentation of pregnancy associated conditions, such as Pre-Eclampsia (PET), Acute Fatty Liver of Pregnancy (AFLP) and HELLP Syndrome (Haemolysis Elevated Liver enzymes Low Platelets). In 94% of identified cases with available data, there was an indicator in the patient history regarding exposure that could have helped include leptospirosis in the clinician’s differential diagnosis. We also identified a range of suitable antibiotic therapies for treating leptospirosis in pregnancy, most commonly used were penicillins.

          Conclusion

          This is the first systematic review of leptospirosis in pregnancy and it clearly shows the need to improve early diagnosis and treatment by asking early, treating early, and reporting well. Ask early—broaden differential diagnoses and ask early for potential leptospirosis exposures and risk factors. Treat early—increase index of suspicion in pregnant patients with fever in endemic areas and combine with rapid field diagnosis and early treatment. Report well—need for more good quality epidemiological studies on leptospirosis in pregnancy and better quality reporting of cases in literature.

          Author summary

          There are more than 1 million cases of leptospirosis in the general population each year. Leptospirosis is an emerging infectious disease and as the world’s environment changes with more floods and environmental disasters, the impact of leptospirosis on the world is expected to increase. Leptospirosis is a zoonotic disease passed onto humans and can cause a range of illness from mild symptoms to severe organ failure and death. It is typically underreported and understudied, hence its classification as a ‘Neglected Tropical Disease’. This is the first systematic review on Leptospirosis in Pregnancy looking at how common it is in pregnancy, how it affects maternal and fetal outcomes, and options for management. We found there to be overlap between how leptospirosis presents in the general population and in pregnancy, and that it can mimic non-infectious conditions that only present in pregnancy such as Pre-Eclampsia, Acute Fatty Liver of Pregnancy and other syndromes where liver and platelet function is affected. Adverse fetal outcomes were found to be more common in pregnant patients who presented in the second trimester compared with patients who presented in the third trimester. In 94% of identified cases with available data, there was a clue in the patient’s history that could have indicated possible exposure to leptospirosis, which is very important in raising suspicion of a diagnosis of leptospirosis in pregnancy. We also identified a range of suitable antibiotic therapies for treating leptospirosis in pregnancy, most commonly used were penicillins. Our recommendations are: Ask early—broaden differential diagnoses and ask early for potential leptospirosis exposures and risk factors. Treat early—combine considering leptospirosis as a cause of fever in pregnant patients in endemic areas with prompt diagnosis and treatment. Report well—there is a need for more good quality epidemiological studies on leptospirosis in pregnancy and better quality reporting of cases in literature.

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          Most cited references51

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          The 2020 report of The Lancet Countdown on health and climate change: responding to converging crises

          For the Chinese, French, German, and Spanish translations of the abstract see Supplementary Materials section.
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            Methodological quality and synthesis of case series and case reports

            Case reports and case series are uncontrolled study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. In this guide, we present a framework for appraisal, synthesis and application of evidence derived from case reports and case series. We propose a tool to evaluate the methodological quality of case reports and case series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest using evidence derived from case reports and case series to inform decision-making when no other higher level of evidence is available.
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              Global Morbidity and Mortality of Leptospirosis: A Systematic Review

              Background Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis is a life-threatening disease and recognized as an important cause of pulmonary haemorrhage syndrome, the lack of global estimates for morbidity and mortality has contributed to its neglected disease status. Methodology/Principal Findings We conducted a systematic review of published morbidity and mortality studies and databases to extract information on disease incidence and case fatality ratios. Linear regression and Monte Carlo modelling were used to obtain age and gender-adjusted estimates of disease morbidity for countries and Global Burden of Disease (GBD) and WHO regions. We estimated mortality using models that incorporated age and gender-adjusted disease morbidity and case fatality ratios. The review identified 80 studies on disease incidence from 34 countries that met quality criteria. In certain regions, such as Africa, few quality assured studies were identified. The regression model, which incorporated country-specific variables of population structure, life expectancy at birth, distance from the equator, tropical island, and urbanization, accounted for a significant proportion (R2 = 0.60) of the variation in observed disease incidence. We estimate that there were annually 1.03 million cases (95% CI 434,000–1,750,000) and 58,900 deaths (95% CI 23,800–95,900) due to leptospirosis worldwide. A large proportion of cases (48%, 95% CI 40–61%) and deaths (42%, 95% CI 34–53%) were estimated to occur in adult males with age of 20–49 years. Highest estimates of disease morbidity and mortality were observed in GBD regions of South and Southeast Asia, Oceania, Caribbean, Andean, Central, and Tropical Latin America, and East Sub-Saharan Africa. Conclusions/Significance Leptospirosis is among the leading zoonotic causes of morbidity worldwide and accounts for numbers of deaths, which approach or exceed those for other causes of haemorrhagic fever. Highest morbidity and mortality were estimated to occur in resource-poor countries, which include regions where the burden of leptospirosis has been underappreciated.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                14 September 2021
                September 2021
                : 15
                : 9
                : e0009747
                Affiliations
                [1 ] National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom
                [2 ] King’s College Hospital NHS Foundation Trust, London, United Kingdom
                [3 ] Bodleian Health Care Libraries, University of Oxford, Oxford, United Kingdom
                Tangen Biosciences, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-5866-2803
                https://orcid.org/0000-0002-6098-7842
                https://orcid.org/0000-0002-1142-6440
                https://orcid.org/0000-0003-0660-5054
                Article
                PNTD-D-21-00588
                10.1371/journal.pntd.0009747
                8462732
                34520461
                f6d583c7-2f94-44a6-92be-f52eb5c86c3a
                © 2021 Selvarajah 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
                : 29 April 2021
                : 20 August 2021
                Page count
                Figures: 2, Tables: 8, Pages: 25
                Funding
                Funded by: Medical Research Council
                Award ID: MR/P022030/1
                Award Recipient :
                The systematic review and MN was funded by a Medical Research Council Career Development Award to Manisha Nair (Grant Ref: MR/P022030/1). The funders had no role in the study design, data collection, analysis or writing of the report.
                Categories
                Research Article
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Bacterial Diseases
                Leptospirosis
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
                Neglected Tropical Diseases
                Leptospirosis
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Zoonoses
                Leptospirosis
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Pregnancy
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Pregnancy
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibiotics
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Case Series
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Liver Disease and Pregnancy
                Medicine and Health Sciences
                Epidemiology
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Fevers
                Custom metadata
                vor-update-to-uncorrected-proof
                2021-09-24
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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