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
Authors: Wilder-Smith Annelies , Wei Yinghui , Araújo Thalia Velho Barreto de , VanKerkhove Maria , Turchi Martelli Celina Maria , Turchi Marília Dalva , Teixeira Mauro , Tami Adriana , Souza João , Sousa Patricia , Soriano-Arandes Antoni , Soria-Segarra Carmen , Sanchez Clemente Nuria , Rosenberger Kerstin Daniela , Reveiz Ludovic , Prata-Barbosa Arnaldo , Pomar Léo , Pelá Rosado Luiza Emylce , Perez Freddy , Passos Saulo D. , Nogueira Mauricio , Noel Trevor P. , Moura da Silva Antônio , Moreira Maria Elisabeth , Morales Ivonne , Miranda Montoya Maria Consuelo , Miranda-Filho Demócrito de Barros , Maxwell Lauren , Macpherson Calum N. L. , Low Nicola , Lan Zhiyi , LaBeaud Angelle Desiree , Koopmans Marion , Kim Caron , João Esaú , Jaenisch Thomas , Hofer Cristina Barroso , Gustafson Paul , Gérardin Patrick , Ganz Jucelia S. , Dias Ana Carolina Fialho , Elias Vanessa , Duarte Geraldo , Debray Thomas Paul Alfons , Cafferata María Luisa , Buekens Pierre , Broutet Nathalie , Brickley Elizabeth B. , Brasil Patrícia , Brant Fátima , Bethencourt Sarah , Benedetti Andrea , Avelino-Silva Vivian Lida , Ximenes Ricardo Arraes de Alencar , Alves da Cunha Antonio , Alger Jackeline 
Published: June 2019

IntroductionZika 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 analysisWe 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 disseminationThe 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 numberPROSPERO International prospective register of systematic reviews (CRD42017068915).