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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
  1. Annelies Wilder-Smith1,
  2. Yinghui Wei2,
  3. Thalia Velho Barreto de Araújo3,
  4. Maria VanKerkhove4,
  5. Celina Maria Turchi Martelli5,
  6. Marília Dalva Turchi6,
  7. Mauro Teixeira7,
  8. Adriana Tami8,
  9. João Souza9,
  10. Patricia Sousa10,
  11. Antoni Soriano-Arandes11,
  12. Carmen Soria-Segarra12,
  13. Nuria Sanchez Clemente13,
  14. Kerstin Daniela Rosenberger14,
  15. Ludovic Reveiz15,
  16. Arnaldo Prata-Barbosa16,
  17. Léo Pomar17,
  18. Luiza Emylce Pelá Rosado18,
  19. Freddy Perez19,
  20. Saulo D. Passos20,
  21. Mauricio Nogueira21,
  22. Trevor P. Noel22,
  23. Antônio Moura da Silva23,
  24. Maria Elisabeth Moreira24,
  25. Ivonne Morales14,
  26. Maria Consuelo Miranda Montoya25,
  27. Demócrito de Barros Miranda-Filho26,
  28. Lauren Maxwell27,28,
  29. Calum N. L. Macpherson22,
  30. Nicola Low29,
  31. Zhiyi Lan30,
  32. Angelle Desiree LaBeaud31,
  33. Marion Koopmans32,
  34. Caron Kim33,
  35. Esaú João34,
  36. Thomas Jaenisch14,
  37. Cristina Barroso Hofer35,
  38. Paul Gustafson36,
  39. Patrick Gérardin37,38,
  40. Jucelia S. Ganz39,
  41. Ana Carolina Fialho Dias7,
  42. Vanessa Elias40,
  43. Geraldo Duarte41,
  44. Thomas Paul Alfons Debray42,
  45. María Luisa Cafferata43,
  46. Pierre Buekens44,
  47. Nathalie Broutet45,
  48. Elizabeth B. Brickley46,
  49. Patrícia Brasil47,
  50. Fátima Brant7,
  51. Sarah Bethencourt48,
  52. Andrea Benedetti49,
  53. Vivian Lida Avelino-Silva50,
  54. Ricardo Arraes de Alencar Ximenes51,
  55. Antonio Alves da Cunha52,
  56. Jackeline Alger53
  57. Zika Virus Individual Participant Data Consortium
    1. 1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    2. 2Centre for Mathematical Sciences, University of Plymouth, Plymouth, UK
    3. 3Department of Social Medicine, Universidade Federal de Pernambuco, Recife, Brazil
    4. 4Health Emergencies Programme, Organisation mondiale de la Sante, Geneve, Switzerland
    5. 5Department of Collective Health, Institute Aggeu Magalhães (CPqAM), Oswaldo Cruz Foundation, Recife, Brazil
    6. 6Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Brazil
    7. 7Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
    8. 8Department of Medical Microbiology, University Medical Center Groningen, Groningen, The Netherlands
    9. 9Department of Social Medicine, University of São Paulo, São Paulo, Brazil
    10. 10Reference Center for Neurodevelopment, Assistance, and Rehabilitation of Children, State Department of Health of Maranhão, Sao Luís, Brazil
    11. 11Department of Pediatrics, University Hospital Vall d’Hebron, Barcelona, Spain
    12. 12SOSECALI C. Ltda, Guayaquil, Ecuador
    13. 13Department of Epidemiology, University of São Paulo, São Paulo, Brazil
    14. 14Department of Infectious Diseases, Section Clinical Tropical Medicine, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
    15. 15Evidence and Intelligence for Action in Health, Pan American Health Organization, Washington, District of Columbia, USA
    16. 16Department of Pediatrics, D’Or Institute for Research & Education, Rio de Janeiro, Brazil
    17. 17Department of Obstetrics and Gynecology, Centre Hospitalier de l’Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
    18. 18Hospital Materno Infantil de Goiânia, Goiânia State Health Secretary, Goiás, Brazil
    19. 19Communicable Diseases and Environmental Determinants of Health Department, Pan American Health Organization, Washington, District of Columbia, USA
    20. 20Department of Pediatrics, FMJ, São Paulo, Brazil
    21. 21Faculdade de Medicina de Sao Jose do Rio Preto, Department of Dermatologic Diseases, São José do Rio Preto, Brazil
    22. 22Windward Islands Research and Education Foundation, St. George’s University, True Blue Point, Grenada
    23. 23Department of Public Health, Universidade Federal do Maranhão – São Luís, São Luís, Brazil
    24. 24Department of Neonatology, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
    25. 25Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia
    26. 26Faculty of Medical Sciences, University of Pernambuco, Recife, Brazil
    27. 27Reproductive Health and Research, World Health Organization, Geneva, Switzerland
    28. 28Hubert Department of Global Health, Emory University, Atlanta, Georgia, USA
    29. 29Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
    30. 30McGill University Health Centre, McGill University, Montréal, Canada
    31. 31Pediatric Infectious Diseases, Stanford Hospital, Palo Alto, California, USA
    32. 32Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands
    33. 33Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
    34. 34Department of Infectious Diseases, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil
    35. 35Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    36. 36Statistics, University of British Columbia, British Columbia, Vancouver, Canada
    37. 37INSERM CIC1410 Clinical Epidemiology, CHU La Réunion, Saint Pierre, Réunion
    38. 38UM 134 PIMIT (CNRS 9192, INSERM U1187, IRD 249, Université de la Réunion), Universite de la Reunion, Sainte Clotilde, Réunion
    39. 39Children’s Hospital Juvencio Matos, São Luís, Brazil
    40. 40Sustainable Development and Environmental Health, Pan American Health Organization, Washington, District of Columbia, USA
    41. 41Department of Gynecology and Obstetrics, University of São Paulo, São Paulo, Brazil
    42. 42Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
    43. 43Mother and Children Health Research Department, Instituto de Efectividad Clinica y Sanitaria, Buenos Aires, Argentina
    44. 44School of Public Health and Tropical Medicine, Tulane University, New Orleans, USA
    45. 45Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
    46. 46Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
    47. 47Instituto de pesquisa Clínica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
    48. 48Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Carabobo, Bolivarian Republic of Venezuela
    49. 49Departments of Medicine and of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Quebec, Canada
    50. 50Department of Infectious and Parasitic Diseases, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil
    51. 51Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil
    52. 52Department of Pediatrics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
    53. 53Facultad de Ciencias Médicas, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras
    1. Correspondence to Dr Lauren Maxwell; maxwelll{at},{at}


    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).

    • individual participant data meta-analysisis
    • prognosis
    • congenital Zika syndrome
    • Zika Virus
    • Microcephaly
    • risk prediction model

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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    • Contributors NB, CBH, TJ, NL, LM, JS and LR contributed to the initial conception of the study. AB, TD, PG, NL, LM and YW made substantial contributions to the statistical methodology proposed for the IPD-MA. LM wrote the first draft of the protocol. AW-S, YW, TVBA, MV, CMTM, MDT, MT, AT, PS, JPS, AS-A, CSS, AMS, NSC, KDR, LR, APB, LP, LEPR, FP, SP, MN, TN, MEM, IM, MCMM, DBMF, LM, CM, NL, ZL, ADL, MK, CK, EJ, TJ, CH, PG, PG, JG, ACFD, VE, GD, TPAD, MLC, PB, NB, EB, PB, FB, SB, AB, VAS, RAAX, AAC and JA provided substantial revisions to the protocol. All authors approved the final version of the protocol.

    • Funding The development of the IPD-MA protocol was supported by a Wellcome Trust grant to the WHO Department of Reproductive Health and Research Human Reproduction Programme, grant number 206532/Z/17/Z.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Liège Maria Abreu de Carvalho; Rosangela Batista; Ana Paula Bertozzi; Gabriel Carles; Denise Cotrim; Luana Damasceno; Lady Dimitrakis; María Manoela Duarte Rodrigues; Cassia F. Estofolete; Maria Isabel Fragoso da Silveira Gouvêa; Vicky Fumadó-Pérez; Rosa Estela Gazeta; Neely Kaydos-Daniels; Suzanne Gilboa; Amy Krystosik; Véronique Lambert; Milagros García López-Hortelano; Marisa Marcia Mussi-Pinhata; Christina Nelson; Karin Nielsen; Denise M. Oliani; Renata Rabello; Marizelia Ribeiro; Barry Rockx; Laura C. Rodrigues; Silvia Salgado; Katia Silveira; Elena Sulleiro; Van Tong; Diana Valencia; Wayner Vieira de Souza; Luis Angel Villar Centeno; Andrea Zin.

    • Patient consent for publication Not required.

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