# Relative and attributable risks of neurological and perinatal adverse outcomes among children with and without prenatal Zika virus exposure in Northeast Brazil: A prospective cohort study (2015–2018)

## TL;DR

This study compares children exposed to Zika virus in the womb with unexposed children to determine how much more likely they are to have birth and neurological problems.

## Contribution

The study provides the first comparison of relative and attributable risks of adverse outcomes in children with and without prenatal Zika virus exposure.

## Key findings

- Prenatal Zika virus exposure is associated with significantly higher risks of microcephaly, neurological abnormalities, and neuroimaging alterations.
- The attributable risk percent for neuroimaging abnormalities is 95%, indicating most cases are likely caused by Zika exposure.
- Children exposed to Zika in utero have a 22-fold increased risk of neuroimaging abnormalities compared to unexposed children.

## Abstract

Although there has been substantial progress in the characterization of Congenital Zika Syndrome, the lack of a control group in the majority of published studies on Zika virus (ZIKV) infections during pregnancy limits our understanding of, first, the magnitude by which prenatal ZIKV exposure may increase risks of adverse outcomes for offspring and, second, the fraction of abnormalities that are attributable to this exposure.

To overcome this limitation, this study harmonized and integrated data collected prospectively in Recife, Pernambuco, Brazil, from offspring of ZIKV-exposed women in the Microcephaly Epidemic Research Group (MERG) Pregnant Women Cohort and from offspring of ZIKV-unexposed women in the Zika in Infants and Pregnancy (ZIP) Study. We compared the data to estimate the relative risk (RR) and attributable risk percent (AR%) of: (i) adverse birth outcomes including low birth weight (LBW), prematurity and small for gestational age (SGA) and (ii) developmental abnormalities including microcephaly and neurological, ophthalmological, audiological, and neuroimaging alterations.

We observed similar odds of adverse birth outcomes and ophthalmological deficits in ZIKV-exposed and unexposed children. However, as compared to ZIKV-unexposed children, ZIKV-exposed children presented with markedly increased risks of microcephaly (RR, 95%-CI: 3.61, 1.70 to 7.63 AR 72%), neurological abnormalities (RR, 95%-CI: 5.64, 3.04 to 10.47.79AR 82%), audiological screening failures (RR, 95%-CI: 9.20, 2.59 to 32.69 AR 89%), and neuroimaging abnormalities (RR, 95%-CI: 22.06, 2.90 to 167.5; AR 95%). The risk of having concurrent abnormalities was lower than the risk of having just one abnormality. Our results provide new insights into the relative and attributable risks related to prenatal ZIKV exposure and demonstrate that, overall, the risks of congenital abnormalities are elevated among children exposed to ZIKV during pregnancy compared to their ZIKV-unexposed peers.

Since the start of microcephaly epidemic in 2015, knowledge has accumulated regarding the spectrum of clinical manifestations resulting from congenital Zika virus infections and the frequency with which they occur. However, it remains unclear how much higher the risk of abnormalities is among children born to women who were infected with Zika virus during pregnancy when compared with children born to women who were not infected during pregnancy. We compared these two groups and found prenatal ZIKV exposure was associated with markedly increased risks of microcephaly (RR, 95%-CI: 3.61, 1.70 to 7.63, AR 72%), neurological abnormalities (RR, 95%-CI: 5.64, 3.04 to 10.47; AR 82%),), audiological deficits (RR, 95%-CI: 9.20, 2.59 to 32.69; AR 89%), and neuroimaging alterations (RR, 95%-CI: 22.06, 2.90 to 167.5; AR 95%). We found that at least 41% of cases of microcephaly, 67% of cases with neurological alterations and 65% of the cases with CNS imaging alterations among children born to exposed mothers may be attributed to the prenatal ZIKV infection. Overall, these findings underscore the importance of continuing the follow-up of these children to evaluate the long-term consequences of ZIKV infection during pregnancy and reinforce the need to rapidly develop a safe and effective vaccine to prevent congenital ZIKV infections.