#Zika Virus #Infection in #Pregnant Women, #Yucatan, #Mexico (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 8—August 2019 / CME ACTIVITY – Synopsis

Zika Virus Infection in Pregnant Women, Yucatan, Mexico

Yamila Romer  , Nina Valadez-Gonzalez, Silvina Contreras-Capetillo, Pablo Manrique-Saide, Gonzalo Vazquez-Prokopec, and Norma Pavia-Ruz

Author affiliations: Emory University, Atlanta, Georgia, USA (Y. Romer, G. Vazquez-Prokopec); Universidad Autónoma de Yucatan, Yucatan, Mexico (N. Valadez-Gonzalez, S. Contreras-Capetillo, P. Manrique-Saide, N. Pavia-Ruz)

 

Abstract

We report demographic, epidemiologic, and clinical findings for a prospective cohort of pregnant women during the initial phase of Zika virus introduction into Yucatan, Mexico. We monitored 115 pregnant women for signs of active or recent Zika virus infection. The estimated cumulative incidence of Zika virus infection was 0.31 and the ratio of symptomatic to asymptomatic cases was 1.7 (range 1.3–4.0 depending on age group). Exanthema was the most sensitive clinical sign but also the least specific. Conjunctival hyperemia, joint edema, and exanthema were the combination of signs that had the highest specificity but low sensitivity. We did not find evidence of vertical transmission or fetal anomalies, likely because of the low number of pregnant women tested. We also did not find evidence of congenital disease. Our findings emphasize the limited predictive value of clinical features in areas where Zika virus cocirculates with other flaviviruses.

Keywords: Zika Virus; Pregnancy; Yucatan; Mexico.

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#Health #outcomes of young #children born to #mothers who received 2009 #pandemic #H1N1 #influenza #vaccination during #pregnancy: retrospective cohort study (BMJ, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMJ. 2019 Jul 10;366:l4151. doi: 10.1136/bmj.l4151.

Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study.

Walsh LK1,2, Donelle J3, Dodds L4, Hawken S2,3,5, Wilson K2,3,5, Benchimol EI2,3,6, Chakraborty P2,6, Guttmann A3,7,8, Kwong JC3,7,9,10, MacDonald NE4, Ortiz JR11, Sprague AE1,2,6, Top KA4, Walker MC1,2,5, Wen SW2,5, Fell DB12,3,6.

Author information: 1 Better Outcomes Registry & Network, Ottawa, ON, Canada. 2 University of Ottawa, Ottawa, ON, Canada. 3 ICES, Toronto, ON, Canada. 4 Dalhousie University, Halifax, NS, Canada. 5 Ottawa Hospital Research Institute, Ottawa, ON, Canada. 6 Children’s Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, Canada. 7 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 8 Hospital for Sick Children, Toronto, ON, Canada. 9 Public Health Ontario, Toronto, ON, Canada. 10 Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. 11 University of Maryland School of Medicine, Baltimore, MD, USA. 12 University of Ottawa, Ottawa, ON, Canada dfell@cheo.on.ca.

 

Abstract

OBJECTIVE:

To determine whether any association exists between exposure to 2009 pandemic H1N1 (pH1N1) influenza vaccination during pregnancy and negative health outcomes in early childhood.

DESIGN:

Retrospective cohort study.

SETTING:

Population based birth registry linked with health administrative databases in the province of Ontario, Canada.

PARTICIPANTS:

All live births from November 2009 through October 2010 (n=104 249) were included, and children were followed until 5 years of age to ascertain study outcomes.

MAIN OUTCOME MEASURES:

Rates of immune related (infectious diseases, asthma), non-immune related (neoplasms, sensory disorders), and non-specific morbidity outcomes (urgent or inpatient health services use, pediatric complex chronic conditions) were evaluated from birth to 5 years of age; under-5 childhood mortality was also assessed. Propensity score weighting was used to adjust hazard ratios, incidence rate ratios, and risk ratios for potential confounding.

RESULTS:

Of 104 249 live births, 31 295 (30%) were exposed to pH1N1 influenza vaccination in utero. No significant associations were found with upper or lower respiratory infections, otitis media, any infectious diseases, neoplasms, sensory disorders, urgent and inpatient health services use, pediatric complex chronic conditions, or mortality. A weak association was observed between prenatal pH1N1 vaccination and increased risk of asthma (adjusted hazard ratio 1.05, 95% confidence interval 1.02 to 1.09) and decreased rates of gastrointestinal infections (adjusted incidence rate ratio 0.94, 0.91 to 0.98). These results were unchanged in sensitivity analyses accounting for any potential differential healthcare seeking behavior or access between exposure groups.

CONCLUSIONS:

No associations were observed between exposure to pH1N1 influenza vaccine during pregnancy and most five year pediatric health outcomes. Residual confounding may explain the small associations observed with increased asthma and reduced gastrointestinal infections. These outcomes should be assessed in future studies.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PMID: 31292120 DOI: 10.1136/bmj.l4151

Keywords: Pandemic Influenza; H1N1pdm09; Vaccines; Pregnancy.

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#Zika Virus-Immune #Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika #Pathogenesis in #Adult and #Pregnant Mice (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Zika Virus-Immune Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika Pathogenesis in Adult and Pregnant Mice

Byoung-Shik Shim, Young-Chan Kwon, Michael J. Ricciardi, Mars Stone, Yuka Otsuka, Fatma Berri, Jaclyn M. Kwal, Diogo M. Magnani, Cody B. Jackson, Audrey S. Richard, Philip Norris,Michael Busch, Christine L. Curry, Michael Farzan, David Watkins, Hyeryun Choe

Mark R. Denison, Editor

DOI: 10.1128/mBio.00758-19

 

ABSTRACT

Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection.

 

IMPORTANCE

Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.

Keywords: Zika Virus; ADE; Pregnancy; Immunopathology; Animal models.

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#Protective Efficacy of Nucleic Acid #Vaccines Against #Transmission of #Zika Virus During #Pregnancy in Mice (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice

Brett W Jagger, Kimberly A Dowd, Rita E Chen, Pritesh Desai, Bryant Foreman, Katherine E Burgomaster, Sunny Himansu, Wing-Pui Kong, Barney S Graham, Theodore C Pierson, Michael S Diamond

The Journal of Infectious Diseases, jiz338, https://doi.org/10.1093/infdis/jiz338

Published: 01 July 2019

 

Abstract

Zika virus (ZIKV) caused an epidemic of congenital malformations in 2015-2016. Although many vaccine candidates have been generated, few have demonstrated efficacy against congenital ZIKV infection. Here, we evaluated lipid-encapsulated mRNA vaccines and a DNA plasmid vaccine encoding the prM-E genes of ZIKV in mouse models of congenital infection. Although the DNA vaccine provided comparable efficacy against vertical transmission of ZIKV, the mRNA vaccines, including one that minimizes antibody-dependent enhancement of infection, elicited higher levels of antigen-specific long-lived plasma cells and memory B cells. Despite the induction of robust neutralizing antibody titers by all vaccines, breakthrough seeding of the placenta and fetal head was observed in a small subset of type I interferon signaling deficient immunocompromised dams. In comparison, evaluation of one of the mRNA vaccines in a human STAT2-knock-in transgenic immunocompetent mouse showed complete protection against congenital ZIKV transmission. These data will inform ongoing human ZIKV vaccine development efforts and enhance our understanding of the correlates of vaccine-induced protection.

Zika, vaccine, pregnancy, congenital Zika syndrome, vaccine, neutralizing antibody

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Zika virus; Pregnancy; Vaccines; Animal models.

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#Zika Virus Non-Structural Protein 1 Disrupts Glycosaminoglycans and Causes #Permeability in Developing #Human #Placentas (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Zika Virus Non-Structural Protein 1 Disrupts Glycosaminoglycans and Causes Permeability in Developing Human Placentas

Henry Puerta-Guardo, Takako Tabata, Matthew Petitt, Milena Dimitrova, Dustin R Glasner, Lenore Pereira, Eva Harris

The Journal of Infectious Diseases, jiz331, https://doi.org/10.1093/infdis/jiz331

Published: 27 June 2019

 

Abstract

Background

During pregnancy, the Zika flavivirus (ZIKV) infects human placentas, inducing defects in the developing fetus. The flavivirus nonstructural protein 1 (NS1) alters glycosaminoglycans on the endothelium, causing hyperpermeability in vitro and vascular leakage in vivo in a tissue-dependent manner. The contribution of ZIKV NS1 to placental dysfunction during ZIKV infection remains unknown.

Methods

We examined the effect of ZIKV NS1 on expression and release of heparan sulfate (HS), hyaluronic acid (HA), and sialic acid (Sia) on human trophoblast cell lines and anchoring villous explants from first-trimester placentas infected with ZIKV ex vivo. We measured changes in permeability in trophoblasts and stromal cores using a dextran-based fluorescence assay and changes in HA receptor expression using immunofluorescent microscopy.

Results

ZIKV NS1 in the presence and absence of ZIKV increased the permeability of anchoring villous explants. ZIKV NS1 induced shedding of HA and HS and altered expression of CD44 and LYVE-1 HA receptors on stromal fibroblasts and Hofbauer macrophages in villous cores. Hyaluronidase was also stimulated in NS1-treated trophoblasts.

Conclusions

These findings suggest that ZIKV NS1 contributes to placental dysfunction via modulation of glycosaminoglycans on trophoblasts and chorionic villi, resulting in increased permeability of human placentas.

ZIKV NS1, chorionic villi, glycosaminoglycans, permeability, hyaluronic acid, heparan sulfate, hyaluronidase, CD44, LYVE-1, Hofbauer cells

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Flavivirus; Zika Virus; Pregnancy; Viral pathogenesis.

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#EBV and #MS #risk in the #Finnish #Maternity #Cohort (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

Epstein‐Barr virus and multiple sclerosis risk in the Finnish Maternity Cohort

Kassandra L. Munger ScD,  Kira Hongell MD,  Marianna Cortese MD, PhD,  Julia Åivo MD, Merja Soilu‐Hänninen MD, PhD,  Heljä‐Marja Surcel PhD,  Alberto Ascherio MD, DrPH

First published: 21 June 2019 / DOI:  https://doi.org/10.1002/ana.25532

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25532.

 

Abstract

Objective

To determine whether maternal Epstein‐Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring.

Methods

We conducted a prospective nested case‐control study in the Finnish Maternity Cohort (FMC) with serum samples from over 800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n=326) on region and dates of birth, sample collection, and mother’s birth. We used conditional logistic regression to estimate relative risks (RR) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25‐hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC.

Results

Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RRtop vs. bottom quintile=2.44, 95%CI: 1.20‐5.00, p trend=0.004); no associations were found between maternal EBNA‐1, EA‐D, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA‐1 IgG levels had a 3‐fold higher risk of MS (RR=3.21, 95%CI: 2.37‐4.35, p trend <1.11e‐16). These associations were not confounded or modified by 25‐hydroxyvitamin D.

Interpretation

Offspring of mothers with high VCA IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated pre‐diagnostic EBNA‐1 IgG levels is consistent with previous results.

This article is protected by copyright. All rights reserved.

Keywords: EBV; Multiple Sclerosis; Pregnancy; Finland; Neurology.

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#Understanding the #relation between #Zika virus #infection during #pregnancy and adverse #fetal, #infant and #child #outcomes: a protocol … (BMJ Open., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMJ Open. 2019 Jun 18;9(6):e026092. doi: 10.1136/bmjopen-2018-026092.

Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children.

Wilder-Smith A1, Wei Y2, Araújo TVB3, VanKerkhove M4, Turchi Martelli CM5, Turchi MD6, Teixeira M7, Tami A8, Souza J9, Sousa P10, Soriano-Arandes A11, Soria-Segarra C12, Sanchez Clemente N13, Rosenberger KD14, Reveiz L15, Prata-Barbosa A16, Pomar L17, Pelá Rosado LE18, Perez F19, Passos SD20, Nogueira M21, Noel TP22, Moura da Silva A23, Moreira ME24, Morales I14, Miranda Montoya MC25, Miranda-Filho DB26, Maxwell L27,28, Macpherson CNL22, Low N29, Lan Z30, LaBeaud AD31, Koopmans M32, Kim C33, João E34, Jaenisch T14, Hofer CB35, Gustafson P36, Gérardin P37,38, Ganz JS39, Dias ACF7, Elias V40, Duarte G41, Debray TPA42, Cafferata ML43, Buekens P44, Broutet N33, Brickley EB45, Brasil P46, Brant F7, Bethencourt S47, Benedetti A48, Avelino-Silva VL49, Ximenes RAA50, Alves da Cunha A51, Alger J52; Zika Virus Individual Participant Data Consortium.

Collaborators (33): Abreu de Carvalho LM, Batista R, Bertozzi AP, Carles G, Cotrim D, Damasceno L, Dimitrakis L, Duarte Rodrigues MM, Estofolete CF, Fragoso da Silveira Gouvêa MI, Fumadó-Pérez V, Gazeta RE, Kaydos-Daniels N, Gilboa S, Krystosik A, Lambert V, López-Hortelano MG, Mussi-Pinhata MM, Nelson C, Nielsen K, Oliani DM, Rabello R, Ribeiro M, Rockx B, Rodrigues LC, Salgado S, Silveira K, Sulleiro E, Tong V, Valencia D, De Souza WV, Villar Centeno LA, Zin A.

Author information: 1 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. 2 Centre for Mathematical Sciences, University of Plymouth, Plymouth, UK. 3 Department of Social Medicine, Universidade Federal de Pernambuco, Recife, Brazil. 4 Health Emergencies Programme, Organisation mondiale de la Sante, Geneve, Switzerland. 5 Department of Collective Health, Institute Aggeu Magalhães (CPqAM), Oswaldo Cruz Foundation, Recife, Brazil. 6 Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Brazil. 7 Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 8 Department of Medical Microbiology, University Medical Center Groningen, Groningen, The Netherlands. 9 Department of Social Medicine, University of São Paulo, São Paulo, Brazil. 10 Reference Center for Neurodevelopment, Assistance, and Rehabilitation of Children, State Department of Health of Maranhão, Sao Luís, Brazil. 11 Department of Pediatrics, University Hospital Vall d’Hebron, Barcelona, Spain. 12 SOSECALI C. Ltda, Guayaquil, Ecuador. 13 Department of Epidemiology, University of São Paulo, São Paulo, Brazil. 14 Department of Infectious Diseases, Section Clinical Tropical Medicine, UniversitatsKlinikum Heidelberg, Heidelberg, Germany. 15 Evidence and Intelligence for Action in Health, Pan American Health Organization, Washington, District of Columbia, USA. 16 Department of Pediatrics, D’Or Institute for Research & Education, Rio de Janeiro, Brazil. 17 Department of Obstetrics and Gynecology, Centre Hospitalier de l’Ouest Guyanais, Saint-Laurent du Maroni, French Guiana. 18 Hospital Materno Infantil de Goiânia, Goiânia State Health Secretary, Goiás, Brazil. 19 Communicable Diseases and Environmental Determinants of Health Department, Pan American Health Organization, Washington, District of Columbia, USA. 20 Department of Pediatrics, FMJ, São Paulo, Brazil. 21 Faculdade de Medicina de Sao Jose do Rio Preto, Department of Dermatologic Diseases, São José do Rio Preto, Brazil. 22 Windward Islands Research and Education Foundation, St. George’s University, True Blue Point, Grenada. 23 Department of Public Health, Universidade Federal do Maranhão – São Luís, São Luís, Brazil. 24 Department of Neonatology, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. 25 Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. 26 Faculty of Medical Sciences, University of Pernambuco, Recife, Brazil. 27 Reproductive Health and Research, World Health Organization, Geneva, Switzerland. 28 Hubert Department of Global Health, Emory University, Atlanta, Georgia, USA. 29 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 30 McGill University Health Centre, McGill University, Montréal, Canada. 31 Pediatric Infectious Diseases, Stanford Hospital, Palo Alto, California, USA. 32 Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands. 33 Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland. 34 Department of Infectious Diseases, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil. 35 Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 36 Statistics, University of British Columbia, British Columbia, Vancouver, Canada. 37 INSERM CIC1410 Clinical Epidemiology, CHU La Réunion, Saint Pierre, Réunion. 38 UM 134 PIMIT (CNRS 9192, INSERM U1187, IRD 249, Université de la Réunion), Universite de la Reunion, Sainte Clotilde, Réunion. 39 Children’s Hospital Juvencio Matos, São Luís, Brazil. 40 Sustainable Development and Environmental Health, Pan American Health Organization, Washington, District of Columbia, USA. 41 Department of Gynecology and Obstetrics, University of São Paulo, São Paulo, Brazil. 42 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 43 Mother and Children Health Research Department, Instituto de Efectividad Clinica y Sanitaria, Buenos Aires, Argentina. 44 School of Public Health and Tropical Medicine, Tulane University, New Orleans, USA. 45 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 46 Instituto de pesquisa Clínica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil. 47 Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Carabobo, Bolivarian Republic of Venezuela. 48 Departments of Medicine and of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Quebec, Canada. 49 Department of Infectious and Parasitic Diseases, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil. 50 Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil. 51 Department of Pediatrics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 52 Facultad de Ciencias Médicas, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras.

 

Abstract

INTRODUCTION:

Zika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.

METHODS AND ANALYSIS:

We will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.

ETHICS AND DISSEMINATION:

The IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.

TRIAL REGISTRATION NUMBER:

PROSPERO International prospective register of systematic reviews (CRD42017068915).

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

KEYWORDS: Microcephaly; Zika Virus; congenital Zika syndrome; individual participant data meta-analysisis; prognosis; risk prediction model

PMID: 31217315 DOI: 10.1136/bmjopen-2018-026092

Keywords: Zika Virus; Microcephaly; Pregnancy; Zika Congenital Infection; Zika Congenital Syndrome.

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