Interpretation
Reinforcing our findings, four larger cohorts6,7,9,13reported lower estimates of pregnancy losses and/or birth defects
(5-7%) while we detected 8.4% of the combined outcomes with an overall
agreement among our rate of pregnancy losses (4.7%) and these studies
(3-10%). The latter of these cohorts also reported that a laboratory
confirmed postnatal diagnosis of CZS, what was not feasible in this
study, contributes to 47% of adverse outcomes and 61% of severe
adverse outcomes described. A metanalysis of studies encompassing 2941
pregnancies27 estimated a prevalence of 2.3% among
all pregnancies and 2.7% in live births, while a recent review showed
that among fetuses exposed to ZIKV during pregnancy, fetal losses
occurred in 4-7%, microcephaly in 4-6% and CZS in
5-14%2, which are similar to this study findings
(4.7%, 3.3% and 2.9%, respectively).
An inverse association between the gestational age of ZIKV infection and
the severity of fetal outcomes has been reported with the worst outcomes
resulted from first-trimester infection6,7,9,28-30.
However, no study has yet systematically and prospectively approached
the exact gestational age of the ZIKV-infection or explored this as a
continuous variable. Most studies estimated maternal infection by
trimester3,5-9,29-32. Also, only one of the previous
studies13 has ruled out congenital cytomegalovirus
infection based on the detection of CMV-DNA within three weeks of age,
which is an important etiology of CNS abnormalities that might confound
ZIKV data. We demonstrated that severe adverse outcomes were a
consequence of maternal ZIKV infection at < 11 weeks of
gestation. We found no infant with typical CZS whose maternal infection
occurred after 14 weeks gestation. Due to the relatively low number of
affected infants in this cohort, we could not estimate the influence of
potential covariates. Nonetheless, the fact that worst outcomes were
14-fold more likely < 11 weeks of gestation is a very
relevant finding regarding clinical management.
The single study that systematically tested infants born to
ZIKV-infected mothers have estimated a 20-30% maternal-fetal
transmission rate13. However, versus other congenital
infections, confirmation of infant ZIKV infection remains a challenge
because no nucleic acid or serological tests have been validated for
this purpose. Only a portion of infants with the typical CZS phenotype
are positive33. Consequently, figures based on
detection of nucleic acid or antibodies might underestimate the true
vertical transmission rate and all ZIKV-exposed babies should be
considered at risk for potential late consequences. We evaluated a
subgroup of infants without microcephaly or CNS abnormalities to
identify early signs of the disease; 8% of them had potential
neurologic abnormalities. Indeed, CNS structural findings related to
ZIKV infection can be silent in the neonatal period for infants not
submitted to neuroimaging examinations34. However,
less is known about isolated early warning signs of neurological
dysfunctions in young infants without microcephaly and CNS
malformations. Prior work showed that 18%35 to
50%36 infants had neurological findings. However,
some of these infants had obvious CNS abnormalities limiting comparisons
with our study. We continue to follow the infants to confirm the
persistence or appearance of neurodevelopmental findings as suggested by
others12,37. Certainly, upcoming controlled cohort
studies are needed for a better understanding of the long-term adverse
outcomes of infants born to ZIKV-infected pregnant women.