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

Abstract

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).

Zika virus seroprevalence in women who gave birth during Zika virus outbreak in Brazil - a prospective observational study

“…Such conditions provide ideal mosquito habitats, which exacerbated the recent ZIKV outbreak, as well as outbreaks of other arboviruses in Brazil. This puts both inhabitants and travelers at risk [ 10 ] because ZIKV infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies [ 11 ]. It seems a very difficult task to control the mosquito ( Aedes aegipty ) in a region without basic sanitation such as Recife.…”

Zika virus infection in pregnancy and adverse fetal outcomes in São Paulo State, Brazil: a prospective cohort study

“…The scientific community and the World Health Organization (WHO) 20 have called for the urgent analysis of data from all ZIKV pregnancy cohorts to further understand the full spectrum of adverse outcomes associated with this infection in pregnancy; as well as maximise the availability of data for use in future meta-analyses 31 . In response to this call, this prospective cohort study in Jundiaí, São Paulo, compared the prevalence of five well-defined adverse fetal outcomes (i.e., prematurity, low birthweight, small-for-gestational-age, fetal death and microcephaly) in a group of ZIKV-positive and ZIKV-negative women and infants.…”

Vertical Transmission of Zika Virus and Its Outcomes: A Bayesian Synthesis of Prospective Studies

“…Results are awaited from several large, multicentre cohort studies of Zika virus in pregnancy (eg, NCT02856984, and ZIKAlliance, ZIKAction, and ZikaPLAN studies). Statistical plans for pooled data analysis have been, or are being, prepared by the Zika Virus Individual Participant Data Metaanalysis Consortium, 29 the European Commission consortia, and the Brazilian Ministry of Health. In the absence of accurate diagnostics for congenital infection, inference regarding the causal effects of Zika virus in pregnancy can only be made by comparing outcomes in women with and without infection in pregnancy, but-as we have seen-the only available control groups are mixtures of both infected and uninfected women.…”

“…In the absence of accurate diagnostics for congenital infection, inference regarding the causal effects of Zika virus in pregnancy can only be made by comparing outcomes in women with and without infection in pregnancy, but-as we have seen-the only available control groups are mixtures of both infected and uninfected women. In one analysis plan, 29 the intention is to regress the relative risk of adverse outcomes in PCRpositive women relative to PCR negative women against estimates of test sensitivity and specificity. However, it is not clear that metaregression would adjust for test inaccuracy: lack of either sensitivity or specificity will bias relative risks towards a null effect.…”