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Observational Study
. 2025 Aug 30;25(1):903.
doi: 10.1186/s12884-025-07774-y.

Zika in Infants and Pregnancy (ZIP) study: results from a prospective international cohort study of prenatal Zika virus infection and adverse fetal and infant outcomes

Jill Farnell Lebov  1 , Martha Nason  2 , Kristen B Stolka  3 , Ricardo Ximenes  4 , Marisa M Mussi-Pinhata  5 , Jack Moye  6 , Carmen D Zorrilla  7 , Carmen M Velez Vega  8 , José F Cordero  9 , Deolinda M F Scalabrin  10   11 , Albert I Ko  10   11 , Maria Elisabeth Lopes Moreira  12 , Luiz Augusto Galvão  13 , William Britt  14 , Ernesto T A Marques  15   16 , Angel Balmaseda  17 , Eva Harris  18 , Juan F Arias  19 , Stacey Schultz-Cherry  20 , Ana Lucía Garces  21 , Nancy F Krebs  22 , Theresa J Ochoa  23 , César Augusto Ugarte-Gil  23   24 , Elizabeth Fogleman  3 , Erin Gabriel  25 , Michael Welton  9 , Carmen M Irizarry  26 , Silvia Biason de Moura Negrini  5 , Conrado Milani Coutinho  5 , Demócrito de Barros Miranda-Filho  27 , Ulisses Ramos Montarroyos  27 , Marli Tenorio Cordeiro  16 , Anna Gajewski  28 , Jorge E Osorio  29 , Lester Figueroa  21
Affiliations
Observational Study

Zika in Infants and Pregnancy (ZIP) study: results from a prospective international cohort study of prenatal Zika virus infection and adverse fetal and infant outcomes

Jill Farnell Lebov et al. BMC Pregnancy Childbirth. .

Abstract

Background: Before Zika virus (ZIKV) infections were observed in the Americas, an association between ZIKV and microcephaly or other congenital malformations was not well documented. Initial reports suggested strong associations between ZIKV and congenital malformations, but plausible estimates of causal effects from prospective studies with adequate sample size and covariate data were few.

Methods: From 2016-2018, the Zika in Infants and Pregnancy (ZIP) study enrolled pregnant people before 18 weeks gestation or with confirmed symptomatic ZIKV in a prospective cohort across 10 sites in South and Central America, and in Puerto Rico. Pregnancies were followed monthly through delivery and 6 weeks postpartum. Infants were followed quarterly to age 12 months. Prespecified co-primary analyses evaluated the associations between a composite endpoint of adverse fetal, neonatal, and infant outcomes with intrauterine ZIKV exposure overall and with symptomatic intrauterine ZIKV exposure. Secondary analyses separately evaluated the association of intrauterine ZIKV exposure with individual components of the primary endpoint.

Results: Six thousand one hundred pregnant participants were included in the primary analysis, including 61 with ZIKV infection during pregnancy confirmed by a ZIKV-specific RNA test. For the primary analyses, the relative risk (RR) for the composite endpoint associated with any ZIKV exposure was 1.64 (95% CI: 0.65, 4.13) and with symptomatic ZIKV exposure 1.08 (95% CI: 0.15, 7.64). Sensitivity analyses provided similar results. Secondary analyses showed significant adjusted RRs [95% CI] for stillbirth (4.28 [1.39, 13.21]), infant death within six weeks (6.20 [1.08, 35.60], and fetal loss before 20 weeks (3.72 [1.82, 7.59]).

Conclusions: The ZIP study identified an elevated but not statistically significant risk of the primary composite outcome with intrauterine ZIKV exposure, and a significantly increased risk of some adverse fetal and infant outcomes with intrauterine ZIKV exposure in secondary analyses. Fewer than expected infections observed during pregnancy, coincident with a waning epidemic, limited study power to evaluate risk. Combining data from multiple cohorts for future meta-analysis may better define the risks of intrauterine ZIKV exposure.

Trial registration: NCT02856984. Registered August 5, 2016. Retrospectively registered.

Keywords: Fetal; Latin America; Microcephaly; Neonatal outcomes; Pregnancy; Zika virus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All participating institutions provided ethical review and approval of the study prior to study initiation. Participants provided written informed consent to participate in the study. Age of minority varied by country and sites followed local IRB/IEC requirements for enrollment of minors in the study. If the participant was considered a minor in the participating country, written permission was required from the parent(s)/legal guardian and separate written assent was required from the participating minor. If not possible to obtain written consent, permission, or assent, e.g., due to illiteracy, pregnant participants and their parent(s)/guardian, as appropriate, provided consent, permission, or assent using a fingerprint instead of a signature. The ethics committees of the following institutions provided approval for this study: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz (Fiocruz Pernambuco); Hospital Geral Roberto Santos; Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz Bahia); Yale University; Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; University of Alabama at Birmingham; Secretaria Municipal de Saúde do Rio de Janeiro; Instituto Fernandes Figueira, Fundação Oswaldo Cruz (Fiocruz – Rio de Janeiro); University of Wisconsin, Madison; St. Jude Children’s Research Hospital; Universidad de Antioquia, Medellín; Red de Salud de Ladera Empresa Social del Estado; University of Colorado, Denver; Instituto de Nutrición de Centro América y Panamá; Ministerio de Salud Pública y Asistencia Social, Guatemala; Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Nicaragua; University of California, Berkeley; University of Puerto Rico, Medical Sciences Campus; University of Georgia, Athens; Hospital Iquitos César Garayar Garcia; Hospital Regional de Loreto Felipe Arriola Iglesias; and Universidad Peruana Cayetano Heredia, RTI International. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Primary and secondary outcome definitions by data source and visit Abbreviations: HC: Head circumference; SD: standard deviation 1 The protocol specified head circumference measurement at birth with confirmation by physical examination between 12 and 24 h by the participating neonatologist. Standard deviation scores (Z-scores) were determined from the Intergrowth reference standard appropriate for sex and gestational age through the birth visit (https://intergrowth21.tghn.org/standards-tools/) and for post-birth visits from WHO child growth standards for sex and age (https://www.who.int/tools/child-growth-standards/standards/head-circumference-for-age) 2 Categorized based on EUROCAT guide 1.4, Sect. 3.5 (https://eu-rd-platform.jrc.ec.europa.eu/sites/default/files/Full_Guide_1_4_version_28_DEC2018.pdf), to determine whether a finding is a major congenital malformation. The definition does not include microcephaly and malformations considered to be minor using the EUROCAT guide 3 Includes observation of a single adverse fetal outcome at birth and at least one subsequent infant assessment visit, or observation of these fetal outcomes in combination at birth; does not include microcephaly or other major congenital outcomes previously defined 4 Infants that failed the audiological screening exam during at least one study visit 5 Infants that failed the ophthalmological screening exam during at least one study visit 6 Data reviewed independently by three clinicians to determine if participant had one or more of the outcomes. Where discordance occurred, meetings were held to come to consensus
Fig. 2
Fig. 2
Disposition of screened individuals. 1Only one pregnancy per participant was planned for inclusion in analysis
See this image and copyright information in PMC

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