Zika causes abnormality in almost a third of the children of women infected during pregnancy

The largest and most comprehensive meta-analysis ever conducted to date on the effects of the Zika virus on children of women infected during pregnancy was published in The Lancet Regional Health – Americas. Based on 13 national studies that gather data from 1,548 pregnant women, the article reaches robust conclusions, such as that almost a third of children present some abnormality as a result of the infection and 4% manifest microcephaly itself. With this, it lays the foundations for assertive public policies, better care and for prioritization from the point of view of new research.

In 2015, when the explosion of cases of microcephaly in children was associated with Zika and the Ministry of Health declared a national emergency, Brazilian researchers were forced to step up their pace to provide answers about the epidemic as quickly as possible.

“Faced with this, there was no time for a large national articulation and different groups conducted independent studies”, recalls epidemiologist Ricardo Arraes de Alencar Ximenes, one of the authors of the research and professor of the Graduate Program in Tropical Medicine at the Federal University of Pernambuco (UFPE ). This spray resulted in smaller patient samples, protocols with disparate criteria and variability of results, which increased uncertainties about the findings.

“But already in 2016 we started talking to these groups to harmonize the protocols and, from then on, consolidate the data from the different studies. Brazilian science has shown its maturity and capacity in this epidemic”, emphasizes Ximenes, who is also a professor at the postgraduate degree in Health Sciences from the University of Pernambuco.

From these interactions, the Brazilian Consortium of Zika Cohorts emerged, which today has scientists from 26 institutions and which enabled the recently released meta-analysis. “The great value of the article, the first of the consortium, is the joining of forces, which allows reaching more reliable results”, highlights the expert.

The work was supported by FAPESP through six projects: (16/08578-0, 17/21688-1, 13/21719-3, 16/15021-1, 15/12295-0 and 16/05115-9 ).

Systematization of knowledge

To be included in the meta-analysis, studies had to have confirmed the diagnosis of Zika infection in pregnant women through RT-PCR tests, considered the most reliable, before any abnormality was detected in the fetus. They also needed to have been conducted in Brazil and accompany the women and their children until at least the end of the pregnancy.

The studies included in the review covered the four regions most affected by the zika epidemic —Northeast, North, Midwest and Southeast.

Data from each participant were analyzed individually and organized into a series of possible outcomes caused by the virus in children. They ranged from low birth weight to microcephaly to ophthalmological and neurological issues such as seizures.

Ximenes points out that, as the zika epidemic was detected by the increase in cases of microcephaly, part of the population still believes that this is the single most worrying abnormality linked to the infection. However, he reiterates that the congenital syndrome linked to the virus can manifest itself in different ways, which include vision difficulties and motor deficits, among others.

Considering the episodes of microcephaly and neurological, ophthalmological and neuroimaging abnormalities (alterations in exams that target the brain), alterations were found in 31.5% of the children —almost a third of the sample. “It is not a surprise to find such a high number, but now we have greater confidence in it”, says Ximenes.

Virologist Maurício Lacerda Nogueira, professor at the Faculty of Medicine of São José do Rio Preto (Famerp) and member of the Brazilian Consortium of Zika Cohorts, considers that pregnant women and children were overrated precisely because they participated in the research: “This generates a detection above average of minor changes, which might have gone unnoticed”.

It is possible, for example, that a brain abnormality found in the meta-analysis was asymptomatic, or caused only mild symptoms. “Regardless of that, one-third of children affected is a very impressive figure, which shows the potential of zika”, he adds.

Furthermore, Ximenes argues that even minor demonstrations can, over the years, trigger problems.

the microcephaly

According to the meta-analysis, 2.6% of the children of infected mothers had microcephaly in the first medical evaluation. However, other children received the same diagnosis over time – in total, 4% manifested the condition during the first years of life.

“Our results indicate that, among children with microcephaly, the fraction diagnosed late is not negligible”, say the authors in the article. “The risk of postnatal Zika-associated microcephaly has not been documented before. This demonstrates the relevance of monitoring the head growth of all children exposed to the virus before birth, even if they have a normal head circumference at birth.” , wrap up.

Incidentally, children with microcephaly associated with Zika tend to have different disorders simultaneously. “This led people to believe that the congenital syndrome linked to zika is characterized, as a rule, by a series of problems”, says Ximenes. “But that doesn’t actually happen in most cases.”

According to the meta-analysis, less than 1% of children affected by the mother’s infection exhibited more than one abnormality. “That is, we found that the manifestations tend to appear in isolation”, reiterates the epidemiologist.

The discovery serves as a warning even for professionals, who sometimes may not relate a condition to zika —or even let it pass— because it is an isolated symptom. “And the early diagnosis of the syndrome enables early interventions, which benefit patients”, says Ximenes.

Associated factors?

As the zika epidemic progressed, it began to be assessed whether some factors would modulate the risk of microcephaly caused by the infection during pregnancy. Dengue, use of larvicides and even socioeconomic issues were raised as possible catalysts for these complications.

“This happened because many cases of microcephaly were detected in the Northeast, but not so many in other regions. So it was postulated that some factor linked to poverty would influence the association between zika and these abnormalities”, clarifies Ximenes.

However, this hypothesis lost strength with the publication of the meta-analysis in question. “The risk [de microcefalia após infecção por zika na gestação] was similar in all places studied and in different socioeconomic conditions. This indicates that there are probably no other factors modifying this association”, points out the article.

That is, the concentration of cases of microcephaly in the Northeast is simply a result of the greater number of infections. “Where there is poverty, there are more mosquitoes”, highlights Ximenes. “In many municipalities in the Northeast, water is not supplied daily. So the population needs to store water, which increases mosquito breeding sites”, he adds.

Nogueira adds that, as the Northeast was the first region to be affected by zika in Brazil, the local population was the one that suffered most from the lack of information. “When the virus arrived in the interior of São Paulo, for example, there was already more news and even recommendations such as avoiding pregnancies, which obviously avoided cases of microcephaly.”

He, by the way, guided a study that ruled out the hypothesis that a previous dengue infection would increase the risk of microcephaly after zika (read more here).

Next steps

“Perhaps the greatest limitation of our work is the lack of a control group”, says Ximenes. This absence is justifiable, as the studies included in the meta-analysis were those conducted during the Zika epidemic and, therefore, needed to provide quick answers. Anyway, future surveys can make comparisons with children whose mothers were not infected with the virus during pregnancy to consolidate or improve the findings.

The authors of the meta-analysis suggest at least two paths in the article that future research can follow: an in-depth investigation, with advanced diagnostic methods, to identify complications that may appear or become more evident in children with microcephaly, in addition to deaths and hospitalizations; and, in children without microcephaly, it would be possible to study the risk of manifestations related to behavioral and neuropsychomotor development that would be diagnosed with advancing age, based on specific tools.

Furthermore, Ximenes and Nogueira agree that the data from this work reinforce the need for constant monitoring of zika. And for that, research centers and authorities must prioritize the development of accurate and cheap tests to diagnose the virus.

“Its use would help to minimize the risk of new infections spreading and causing waves of disease and complications”, Ximenes reasons.

It would be possible, for example, to use these tests to carry out active surveillance in strategic locations or specific population groups. From then on, public authorities would adopt control measures to prevent outbreaks and epidemics.

It is also important to remember that, in addition to these strategies, public interventions to improve the living conditions of the population, sanitation and mosquito control can be more effective and have a lasting effect to reduce the risk of transmission.

Efforts should also be focused on creating a Zika vaccine. “There are national and international works in progress that can contribute to defining an ideal composition of this immunizer. But it will take years before this vaccine candidate is reached, so that we can begin to evaluate its safety and efficacy”, estimates Nogueira.

At the same time, Ximenes gives the message that the children of mothers infected during pregnancy should be evaluated at least once by specialists and closely monitored even if they have not shown symptoms. “Moreover, the epidemic will go away, but the children will remain. We need to take good care of them and do everything to alleviate their problems”, he adds.

Will you come again?

Attention to Zika has waned, especially during the Covid-19 pandemic. Both Nogueira and Ximenes agree that this is understandable, not least because laboratories had to dedicate themselves to SARS-CoV-2 and the tremendous impact it had on society.

But the truth is that new episodes of Zika-associated congenital syndrome have also decreased. If in 2015 and 2016, 12,716 suspected cases were reported, in 2022 the number was 419, according to the September Epidemiological Bulletin of the Ministry of Health.

Of the cases identified last year, 76% are still under investigation, but only one has been confirmed — and the child was born in 2016.

“This is part of the natural dynamics of diseases transmitted by vectors such as mosquitoes. They come, cause an epidemic and then disappear for a period”, analyzes Nogueira. “Now, we may not be seeing zika anymore because we are not doing tests either. Only pregnant women or patients with neurological symptoms are currently being evaluated”, she ponders.

The Famerp virologist explains that the ups and downs of cases of arboviruses is multifactorial. The numbers may drop because part of the population developed immunity for a short period of time after being exposed, due to some cross-reaction with another virus (such as dengue), due to adaptation to mosquitoes that work as vectors, etc.

“It is a complex phenomenon, which we even studied in our group. But I believe that in a few years we may have an increase in cases of zika and, with it, in its complications”, he warns.

Given this forecast, he reinforces the need for a vaccine and new tests, in addition to encouraging measures to raise public awareness about zika and other arboviruses.

The study 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 can be accessed here.