Adverse fetal and perinatal outcomes associated with Zika virus infection during pregnancy: an individual participant data meta-analysis

Edna Acosta Pérez ; Juan Aguilar Ticona ; Jackeline Alger ; Celia Alpuche Aranda ; Angélica Amado Niño ; Emily Ansusinha ; Thalia Araújo ; Juan Arias ; Lumumba Arriaga Nieto ; Marcos Ávila ; +173 more... Azucena Bardají ; Carlos Becerra Mojica ; Andrea Benedetti ; Ana Bertozzi ; Sarah Bethencourt ; Karen Blackmon ; Victor Borja Aburto ; Patrícia Brasil ; Elizabeth Brickley

; William Britt ; Nathalie Broutet ; Pierre Buekens ; André Cabié ; David Alejandro Cabrera-Gaytán ; Rodrigo Cachay ; Maria Luisa Cafferata ; Isaac Caicedo-Castro ; Juan Calle ; Guilherme Calvet ; Harlan Campbell ; Maribel Campos ; Mabel Carabali ; Helen Cerigo ; Celia Cordon ; Juliana Silva Corrêa ; Federico Costa ; Conrado Coutinho ; Antonio Cunha ; Carlos Cure Cure ; Johanna Damen ; Marcela Daza ; Ilich De la Hoz Siegler ; Roberta DeBiasi ; Thomas Debray ; Valentijn de Jong ; Camille Delgado-López ; Geraldo Duarte ; Gabriella Duarte Miranda ; Valorie Eckert ; Sophie Eickmann ; Esther Ellis ; Cassia Estofolete ; Lester Figueroa Bolaños ; Olivier Fléchelles ; Kirsten Fong ; Maria Barbara Franco Gomes ; Trevon Fuller ; Victoria Fumadó ; Anna Funk ; Luis Galvão ; Gabriela Lopes Gama ; Patrick Gérardin ; Luz Gibbons ; Anna Goncé ; Amy Gonzalez ; Eduardo Gotuzzo ; Concepción Grajales-Muñiz ; Paul Gustafson ; Tahani Hamdan ; Eva Harris ; Cosme Harrison ; Najeh Hcini ; Cristina Hofer ; Natanaël Holband ; Claudia Hormiga Sánchez ; Ivonne Huerta ; Isabel Hurtado ; Irene Inwani ; David Cruvinel Isaac ; Thomas Jaenisch ; Esaú João ; Amadu Juliana ; Jose Paulo Pereira Junior ; Edna Kara ; Caron Kim ; Albert Ko ; Nancy Krebs ; Angelle Desiree LaBeaud ; Heather Lake-Burger ; Jill Lebov ; Yee-Sin Leo ; Brooke Levis ; Talita Lima ; Simon Ling ; Eduardo Lopez-Medina ; Cynthia Lorenzo ; Calum Macpherson ; Olivia Manders ; Elena Marbán-Castro ; Ernesto Torres de Azevedo Marques ; Celina Turchi Martelli ; Flor Martinez-Espinosa ; Gloria Martinó González ; Gustavo Matta ; Salim Máttar ; Lauren Maxwell ; John McCracken ; Adriana Melo ; Clara Menéndez ; Marcela Mercado Reyes ; María Consuelo Miranda Montoya ; Demócrito de Barros Miranda-Filho ; Ulisses Montarroyos ; Karel Moons ; Maria Elisabeth Moreira ; Jack Moye ; Sarah Mulkey ; José Muñoz-Medina ; Johanna Munoz ; Marisa Mussi-Pinhata ; Silvia Negrini ; Nivison Nery ; Jurg Niederbacher Velásquez ; Karin Nielsen ; M Kariuki Njenga ; Trevor Noël ; Mauricio Nogueira ; Theresa Ochoa ; Consuelo Oliveira ; Eric Osoro ; Ester Paiva Souto ; Miguel Parra-Saavedra ; Saulo Passos ; Luiza Pela Rosado ; Bernadete Perez Coêlho ; Priscila Cardia Petra ; Léo Pomar ; Arnaldo Prata-Barbosa ; Ingrid Rabe ; Mitermayer G Reis ; Ana Maria Rivera Casas ; Diana Rojas ; Kerstin Daniela Rosenberger ; Paola Mariela Saba Villarroel ; Nuria Sanchez Clemente ; Magda Sanz Cortes ; Janet Sayers ; Deolinda Scalabrin ; Lavinia Schuler-Faccini ; Stacey Schultz-Cherry ; Aluisio Segurado ; Kirstin Short ; Priya Shreedhar ; Antônio Silva ; Ronaldo Silva ; Vivian Avelino Silva ; Isadora Cristina de Siqueira ; Karen Sohan ; Antoni Soriano-Arandes ; Carmen Soria-Segarra ; Paulo Sucasas da Costa ; Adriana Tami ; Jousilene Tavares ; Maria Benamor Teixeira ; Robert F Terry ; Tun-Linn Thein ; Soe Soe Thwin ; Frank Tobian ; Vivian Torres Rodríguez ; Isabel Trejos ; Marilia Dalva Turchi ; César Ugarte-Gil ; Miguel Valencia-Prado ; Alfonso Vallejos-Parás ; Zilton Vasconselos ; Ana Beatriz Gorini da Veiga ; Carmen Viñuela-Benéitez ; Manon Vouga ; Yinghui Wei ; Jamie Westcott ; Marc-Alain Widdowson ; Ricardo Ximenes ; Carmen Zorrilla ; (2025) Adverse fetal and perinatal outcomes associated with Zika virus infection during pregnancy: an individual participant data meta-analysis. EClinicalMedicine, 83. p. 103231. ISSN 2589-5370 DOI: 10.1016/j.eclinm.2025.103231

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Background: Zika virus (ZIKV) infection during pregnancy is associated with an increased risk of congenital malformations. The prevalence of short and long-term consequences, however, remains uncertain due to heterogeneity across studies. Individual Participant Data Meta-Analysis (IPD-MA) offers an alternative approach to provide more precise and generalisable estimates through data harmonisation across studies, allowing for standardised definitions and exploration of heterogeneity. This project was undertaken to estimate absolute and relative risks of adverse outcomes for individuals with ZIKV infection during pregnancy. Methods: IPD-MA studies and their datasets were identified through a systematic search conducted in 2018 with the following criteria: observational longitudinal or surveillance-based studies investigating ZIKV during pregnancy or at birth, measured fetal, infant, or child outcomes, and included at least 10 participants. Here we used IPD data shared by March 2022 from 18 studies from international health organisations and research networks, comprising 24 unique datasets, in 11 countries. Datasets were harmonised with standardised definitions, using variables related to pregnant individuals, methods used for ZIKV diagnoses, fetal characteristics and outcomes, and pooled for analysis. Frequentist and Bayesian regression methods were applied to estimate outcome prevalence and evaluate the association between maternal ZIKV infection and fetal loss, microcephaly and congenital zika syndrome as primary outcomes. Findings: Data including 9568 pregnant individuals and 9608 newborns, were harmonised. The risk of severe primary microcephaly was significantly higher in ZIKV-positive pregnancies (1.5%, CI 0.8%–2.7%) compared to ZIKV-negative ones (0.3%, CI 0.1%–1.0%), with a relative risk of 4.5 (CI 1.5–13.3) in the one-stage meta-analysis. While some risk estimates were consistent between Bayesian and Frequentist methods, estimates for other outcomes varied, underscoring the influence of both the analytical approach and the definition of ZIKV on the associations. Interpretation: Our findings align with previously published meta-analyses and indicate an added burden to adverse pregnancy outcomes with higher prevalence compared to pre-epidemic population-based average values. Future research should focus on additional outcomes with clear definitions of maternal infection. Women of reproductive age should be informed about the risks of Zika infection during pregnancy to support reproductive planning. Funding: This project was supported by the Wellcome Trust grant number 206532/Z/17/Z, the WHO Health Emergencies Programme Global Arbovirus Initiative, and the WHO Department of Sexual and Reproductive Health and Research, including the Human Reproduction Special Programme (HRP).