In 2015, the scientific community was surprised by an epidemic of microcephaly initially
identified in some states in northeastern Brazil. The first observations of an unusual
increase in the number of cases of microcephaly were made by physicians in their clinical
practice. After confirming the occurrence of this new phenomenon, came the challenges
in determining its etiology, characterizing the spectrum of clinical manifestations
and estimating the risk of its occurrence. These stages were successively fulfilled
through ecological studies, case reports and series, and epidemiological studies.[1] Clinicians were the first to raise the hypothesis that Zika virus infection during
pregnancy was responsible for the adverse effects observed in children.[2] Subsequently, the virus was detected and sequenced in the amniotic fluid of two
pregnant women whose fetuses had microcephaly[3] and specific IgM for Zika was detected in the cerebrospinal fluid of children with
microcephaly.[4] A case-control study showed the association between the Zika virus and microcephaly
and at the same time, ruled out the role of other factors that could be responsible
for its occurrence.[5] The follow-up of cohorts of pregnant women allowed estimating the risk for microcephaly,
abnormalities of the Central Nervous System (CNS) diagnosed by imaging, ophthalmologic
and audiologic alterations and other birth defects in children born to Zika virus-infected
mothers during pregnancy.[6]
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[13] Although cohort studies have shown similar risks of microcephaly, estimates of the
risk of other manifestations were diverse, indicating the need to use other analysis
strategies with more robust estimates, such as meta-analysis.
In Brazil, cohort studies were developed by different groups of researchers. However,
since the beginning of the microcephaly epidemic, Brazilian scientists were concerned
about standardizing research protocols and collection instruments as far as possible
to enable a joint data analysis in a later step. Several meetings were held to this
end, initially involving Brazilian researchers and later researchers from different
countries, with support of the Pan American Health Organization and the World Health
Organization. In Brazil, the Zika Brazilian Cohorts (ZBC) Consortium[14] was formed. By performing a joint analysis of data from Brazilian studies, it overcomes
the limitations of isolated studies, notably the small sample size and consequent
inaccuracy of estimates and lower representativeness. Among the contributions of the
ZBC Consortium is the recently published article: “Risk of adverse outcomes in offspring
with RT-PCR confirmed prenatal Zika virus exposure: an individual participant data
meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium.”[15] Next, we will highlight some of its points.
Several factors reinforce the relevance of the results presented in this article.
It is a meta-analysis of individual data that aggregates and analyzes data from different
studies after a process of harmonization of results. Harmonization was performed through
several meetings of researchers and enabled the formation of a single database and
the analysis of information from all participants, differing from traditional meta-analyzes
in which only aggregated data are reanalyzed. The Consortium included almost all cohorts
of pregnant women developed in Brazil, totaling 13 studies performed in four Brazilian
regions where the Zika virus epidemic occurred, namely the North, Northeast, Central
West and Southeast. It is the study with the largest number of participants published
so far, totaling 1,548 pregnant women and their respective gestational outcomes. All
women had Zika virus infection during pregnancy confirmed through RT-PCR, the gold
standard for diagnosing Zika virus infection.[16] Because of interpretation limitations, serological tests were not used to define
exposure.
The results of this ZBC-Consortium meta-analysis provide more robust and accurate
estimates of the risk of adverse events in children born to pregnant women who were
infected with Zika virus during pregnancy. This study answers an important question
for physicians and health professionals by informing the probability of occurrence
of manifestations potentially associated with congenital Zika.
According to the study findings, although microcephaly is the most severe manifestation,
it is not the most frequent, being observed in 1.5% of children at birth, and severe
microcephaly is less frequent than mild/moderate microcephaly. Furthermore, even though
some children are born with a normal head circumference for their age and sex, they
may develop postnatal microcephaly, which implies the need to monitor these children
and repeat head circumference measurements. It was also demonstrated that the risk
of children being born small for gestational age was greater than the risk reported
for the general population. Unlike what had been suggested by some authors, the risk
of microcephaly did not vary in different regions of the country or with different
socioeconomic conditions.
The risk of occurrence of structural changes in the CNS in children born to mothers
who became infected during pregnancy was around 8%, and was observed even in children
without microcephaly. The most frequent were calcifications, ventriculomegaly and
diffuse cortical atrophy, in addition to other manifestations identified. Ultrasound
imaging of the CNS after birth is a valuable tool for diagnosing structural alterations.
The risk of presenting at least one neurological alteration was around 20%, highlighting
the occurrence of changes in tonus/trophism and convulsive crises. The risk of these
alterations (20%) was greater than that of microcephaly and structural abnormalities
in the CNS, showing the complementarity of this information and the need to integrate
them for an adequate and long-term evaluation of these children.
The risks of audiological and ophthalmological adverse effects, especially changes
in the optic nerve, were less than 5%.
Approximately one-third of infants born to mothers exposed to the Zika virus during
pregnancy had at least one change, and less than 1% had concomitant changes.
The risks estimated in the ZBC-Consortium meta-analysis are relevant for planning
care for pregnant women who become infected with the Zika virus during pregnancy and
the care for children born to these mothers. Note that the possibility of a new Zika
virus epidemic cannot be ruled out as the number of susceptible individuals increases.
The study highlights the need for at least one comprehensive assessment of children
by different groups of specialists during their follow-up for the early detection
of abnormalities and definition of the necessary interventions. The study also indicates
the need for long-term monitoring of children to identify the risk of late manifestations.
