{"id":448649,"date":"2022-08-22T19:33:37","date_gmt":"2022-08-22T22:33:37","guid":{"rendered":"https:\/\/revistapesquisa.fapesp.br\/?p=448649"},"modified":"2022-08-22T23:54:48","modified_gmt":"2022-08-23T02:54:48","slug":"children-with-congenital-zika-syndrome-suffer-developmental-delays-in-motor-cognitive-and-language-skills","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/children-with-congenital-zika-syndrome-suffer-developmental-delays-in-motor-cognitive-and-language-skills\/","title":{"rendered":"Children with Congenital Zika Syndrome suffer developmental delays in motor, cognitive, and language skills"},"content":{"rendered":"

In 2015, when Inabela Souza da Silva Tavares fell pregnant with her second child, she did not even consider that the baby might not be born healthy. All she thought about was that she wanted it to be a girl. \u201cMy dream was to have another daughter,\u201d she said during a video call from her home in Recife, the state capital of Pernambuco, in May. She got her wish, and her daughter Graziela was born at the end of the year, about a month premature. An infection that Tavares suffered during pregnancy, however, affected the baby’s health, drastically altering her life and the lives of her entire family. In around the fifth month of her pregnancy, she was hospitalized after waking up one morning with a headache and general body pain. At the hospital, the doctors\u2019 initial diagnosis was dengue fever, which has caused occasional epidemics Brazil since the 1980s. The likelihood is, however, that it was not dengue\u2014or at least, not only dengue. At the time, the Zika virus, a pathogen that originated in Africa and had never been detected in the Americas, and was previously considered harmless, was already circulating silently in Brazil.<\/p>\n

Ultrasound exams carried out in Tavares\u2019s sixth month of pregnancy brought worrying news. First, they indicated that Grazi, as her mother calls her, had a buildup of fluid in the cavities in her brain and between the membranes that protect it. Later, they revealed that her skull was also much smaller than expected for her gestational age. She had congenital microcephaly, a condition with no cure that had never been attributed to dengue fever. Later tests would confirm that while still in the womb, Grazi had been exposed to the Zika virus shortly after it arrived in Brazil. She was born with what would later become known as Congenital Zika Syndrome (CZS). The condition is caused by a wide range of damage to the central nervous system and can hinder a child\u2019s development and independence to varying degrees. Despite her major limitations\u2014Grazi cannot walk or talk and is fed by a tube\u2014she attended day care, which was able to help her thanks to adaptations suggested by her mother, and is now in her first year of elementary school.<\/p>\n

Grazi was not the only child to suffer the harmful effects of the virus. Since 2015, another 1,833 cases of CZS have been officially confirmed in Brazil, one of the countries most affected by Zika\u2014in 2016 alone, the epidemic\u2019s worst year, there were more than 250,000 suspected cases of infection with the virus (see graphs below<\/em>). Since the first occurrences were identified in Brazil, 20,444 suspected cases of CZS have been reported to the Ministry of Health. Of these, 3,017 are still under investigation, according to the February edition of the ministry\u2019s Epidemiological Bulletin<\/em>, the most recent to address the matter. About 90% of children with the syndrome were born in 2015 and 2016, at the height of the epidemic, which subsided in the following years. Most are from states in the Northeast. The oldest are approaching 7 years of age, and as they grow up, certain developmental problems are becoming more evident and better studied by various research groups.<\/p>\n

A paper published in the journal Frontiers in Genetics <\/em>in March this year gave an updated overview on how these children progress in their early years. Led by Dr. Lavinia Sch\u00fcler-Faccini, a geneticist from the Federal University of Rio Grande do Sul (UFRGS), approximately 30 researchers from six Brazilian states analyzed information from just over 160 scientific articles published prior to mid-2021 on the most common clinical manifestations and developmental problems presented by children with the syndrome, in addition to the virus\u2019s potential mechanisms of action. \u201cCZS encompasses a broad range of sensorimotor impairments with multiple health and social effects,\u201d the authors state.<\/p>\n

The syndrome is characterized by the simultaneous occurrence of two or more of six characteristics associated with the virus: smaller than expected head size for age (microcephaly); calcifications in the central nervous system; decreased brain volume; enlargement of brain cavities (ventricles) containing cerebrospinal fluid; damage to the eyes or brain structures associated with vision; and arthrogryposis, a severe form of joint malformation.<\/p>\n<\/div>

\n \n \n \n <\/picture>Rodrigo Cunha<\/span><\/div>
\n

A high proportion of children with CZS (70\u201388%) are born with microcephaly, usually more severe than is seen when caused by infection during pregnancy with five other pathogens, which together form an acronym known to pediatricians and neurologists as STORCH: the syphilis bacteria, the toxoplasmosis protozoa, the rubella virus, the cytomegalovirus, and the herpes virus. In addition to reduced head circumference, the top of the skull of babies with CZS is often smaller, making their faces appear disproportionately large and causing excess folds in the scalp. The symptoms led to impactful images that drew the attention of many when broadcast by the media during the epidemic.<\/p>\n

All of this damage results from the virus’s predilection for infecting and reproducing in the cells of the nervous system. In mid-2016, teams coordinated by neuroscientists Jean Pierre Peron and Patr\u00edcia Beltr\u00e3o Braga from the University of S\u00e3o Paulo (USP) and Stevens Rehen and Patricia Garcez from the Federal University of Rio de Janeiro (UFRJ), together with the D’Or Institute of Research and Teaching (IDOR), found that the virus prefers to invade and damage neural progenitors: cells that act as precursors to different types of brain cells and are abundant in early fetal development. By infecting neural progenitors, Zika takes over the cell and starts producing new copies. The process leads to death of the progenitors in one of two ways: by apoptosis (programmed cell death), in which the cell dies after receiving signals that it will not be able to recover its normal function; and by autophagy, when sacs containing acids and enzymes break down and digest the cellular contents (see<\/em> Pesquisa FAPESP issue<\/em> n\u00ba 244<\/em><\/a>).<\/p>\n

With Zika infections, apoptosis is preceded by derangements that also prevent neural progenitors from multiplying and giving rise to neurons, the cells responsible for processing and storing information, causing the brain to become smaller and to have less of its characteristic folds. More recently, Rehen’s group and another led by Andr\u00e9 Quincozes Santos, a neuroscientist from UFRGS, found that the Zika virus also triggers a toxic inflammation of other brain cells.<\/p>\n

The changes that characterize the syndrome increase the risk of death by up to 14 times, revealed a study published in the New England Journal of Medicine <\/em>in February. Previous studies have indicated that about 10% of children with CZS die in the first years of life. It was not known, however, exactly how much greater the risk is in children with CZS compared to those without the syndrome. Nor was it known how the chance of death is affected by other factors that influence infant mortality, such as pregnancy duration and birth weight. Enny Paix\u00e3o Cruz, an epidemiologist and professor at the London School of Hygiene & Tropical Medicine, UK, and a researcher at FIOCRUZ in Bahia, helped clarify these issues by analyzing the deaths that occurred among 11,481,215 children born in Brazil between January 1, 2015, and December 31, 2018.<\/p>\n

Over the three-year period, the country registered 3,308 children born with CZS and 11,477,907 without it\u2014the number of cases of the syndrome analyzed and confirmed by the Ministry of Health is lower. In the same period, 398 (12%) of the first group and 120,609 (1%) of the second group died. Before the third year of life, the mortality rate in children with CZS was 52.6 deaths per 1,000 children annually and 5.6 deaths per 1,000 children annually among those without the syndrome. The difference was even greater when only looking at babies born after 37 weeks of gestation (14.3 times higher) or weighing more than 2.5 kilograms (12.9 times). \u201cThis risk remained high throughout the first three years of life, which was the period evaluated,\u201d says Cruz.<\/p>\n

Most of the damage is caused by the virus’s predilection for infecting and reproducing in the cells of the nervous system<\/p><\/blockquote>\n

In the first year of life, the main cause of death among children with CZS was congenital deformations, especially microcephaly. From the second year onwards, the death rate due to diseases of the central nervous system (paralysis) and the circulatory system (arrhythmia and heart failure) increases. \u201cWe are now analyzing the causes of death in detail. Knowing this will allow us to improve clinical management for these children,\u201d says the scientist.<\/p>\n

Roughly 80\u2013100% of children with CZS who reach their first birthday have severe cerebral palsy, according to the studies included in the Frontiers in Genetics <\/em>review article. The damage the condition causes to the brain and other organs of the central nervous system leads to muscle stiffness, difficulty controlling posture, and coordination problems. It can also affect speech and the ability to swallow. These children are rarely able to walk unaided. Almost all need to use a wheelchair, although in less severe cases, some are able to move around with the support of special walkers.<\/p>\n

At least six of every 10 develop epilepsy, which is often difficult to control, requiring the use of two, three, or more medications to control the seizures. A similar proportion suffer muscular rigidity and exaggerated movements, as well as retaining so-called primitive reflexes, a set of involuntary movements\u2014sucking, closing their fingers around an object, or turning their head towards a touch to the face, for example\u2014that usually disappear after 6 months of age. Many show no progress in assessments carried out aged two or three.<\/p>\n

In a study led by Ant\u00f4nio Augusto Moura da Silva, an epidemiologist from the Federal University of Maranh\u00e3o (UFMA), physical therapist Eliana Morioka Takahasi analyzed the gross motor skills of 100 children with CZS treated at the Reference Center for Children\u2019s Neurodevelopment, Assistance, and Rehabilitation (NINAR) in S\u00e3o Lu\u00eds, the state capital of Maranh\u00e3o. She ran a series of tests designed to assess their ability to sit, roll, stand, crawl, walk, run, and jump. These activities all involve the use of major muscle groups and are usually mastered by age two in children without CZS or cerebral palsy.<\/p>\n

At the time of the first assessment, the children ranged in age from one year and eight months to two-and-a-half, and 90% of them had the most severe degree of limitation. They had to be carried by their carers or pushed in wheelchairs and had difficulty keeping their torsos upright or holding their heads up, according to the results, published in the journal Neuropediatrics <\/em>in October 2020. Forty-six of them underwent a second assessment between six and eight months later, when they were almost three years old. None showed improvement in their condition. The researchers believe most were close to reaching their motor development limit, well below that of children without the syndrome.<\/p>\n\n \n \n \n <\/picture>Rodrigo Cunha<\/span>\n

Pernambuco, the first state to notice an increase in microcephaly cases in 2015, was one of the most affected in both waves of the epidemic. There were 332 cases of CZS confirmed in the state in 2015 and 64 in 2016, according to a 2018 survey published in the journal Epidemiology and Health Services <\/em>by Giovanny Ara\u00fajo de Fran\u00e7a, an epidemiologist from the Health Surveillance Department at the Ministry of Health. In Recife, speech therapists, occupational therapists, and psychologists from the Professor Fernando Figueira Medical Institute (IMIP), a philanthropic organization, monitored 40 children with CZS born in the period until the beginning of the COVID-19 pandemic. The severity of their conditions varied, but all of them showed limited improvement over time.<\/p>\n

\u201cThe first two years are a window of opportunity for motor development. That’s when the response is fastest. After that, children reach a limit,\u201d says physical therapist Marcela de Oliveira Lima, head of rehabilitation at IMIP. When they grow up with motor difficulties, they can face obstacles to playing and exploring their environment, as well as intellectual delays. \u201cMothers need a lot of help so that they can learn to take care of these children at home and encourage them in the most appropriate ways,\u201d she explains. It was for this reason that the IMIP group developed a booklet containing guidelines and distributed it to parents of children with CZS.<\/p>\n

In Para\u00edba, another state with a significant number of children with CZS, a group led by Altamira Reichert, a nurse from the Federal University of Para\u00edba (UFPB), organized workshops and first-aid booklets to teach the mothers of children treated at the institution how to deal with two of the syndrome\u2019s most common problems: convulsions and choking. After the training was given, 10 mothers were evaluated in a qualitative study to identify the impact on their lives and on their children. The results, presented in the journal Applied Nursing Research <\/em>in 2021, indicate that the training gave mothers independence and confidence to act in the event of choking or seizures, where previously they adopted ineffective or even harmful measures. \u201cWe observed that even mothers without a high level of education, if well guided, can adequately take care of their children in these situations,\u201d says Reichert.<\/p>\n

In addition to a marked delay in motor development, children with the syndrome also have problems with cognition and language. In Bahia, another state with a high number of Zika cases during the epidemic, Alessandra Carvalho, a pediatrician from the SARAH Network of Rehabilitation Hospitals in Salvador, subjected 82 one-year-old children with CZS-associated cerebral palsy to a series of tests. According to the results, published in the journal Brain & Development<\/em> in 2019, all showed extremely low performance in three areas: cognition, language, and motor skills.<\/p>\n

In more recent research, psychologists Anne Wheele and Donald Bailey Jr, of the Research Triangle Institute in the USA performed the same tests on 121 slightly older children with CZS aged around two-and-a-half. The children were all receiving care from the Altino Ventura Foundation, a philanthropic organization based in Recife that has helped 344 children with the syndrome since 2015. The foundation is currently providing medical care to 148 of them\u2014including Grazi\u2014as well as speech therapy, physiotherapy, occupational therapy, and psychology.<\/p>\n<\/div>

\n \n \n \n <\/picture>Rodrigo Cunha<\/span><\/div>
\n

The children tested performed poorly once again. At two-and-a-half years old, most had skills comparable to babies aged two or three months, the researchers reported in the journal JAMA Network Open<\/em> in May 2020.<\/p>\n

In terms of cognition, three out of four reacted to sounds and recognized their caregiver (almost always the mother), but only 20% were able to engage with and explore objects, while an even smaller proportion (10%) demonstrated the ability to solve a problem (finding something that had fallen). About half were able to follow an object with their eyes or by moving their head and even hold it if it was placed in their hands. Only 8%, however, were able to grasp objects on their own. A large proportion (61%) were able to control their neck and head while being carried, but only two children could walk unaided and two others were able to crawl.<\/p>\n

They fared better in the receptive language assessment, performing similarly to children just over one-and-a-half years old on average. Almost all of them reacted to ambient sounds and a third of them responded to their own name, but only one was able to recognize the objects by name. Two of the children could express themselves using words and another nine were able to babble or imitate sounds.<\/p>\n

In Bahia, a group led by Albert Ko, an epidemiologist from the Yale School of Public Health, USA, and a visiting researcher at FIOCRUZ\u2019s Gon\u00e7alo Muniz Institute, is monitoring some 400 children who were exposed to the Zika virus during pregnancy, of whom 42 developed CZS. In an analysis published in the journal PLOS ONE<\/em> in 2021, Ko and his colleagues wrote that almost all of the children with the syndrome have significant delays in cognitive, motor, and language development. Their patterns of development, however, are surprisingly heterogeneous. \u201cIt’s still a challenge to understand these results,\u201d Ko said.<\/p>\n

Caring for children with Congenital Zika Syndrome is a complex task. They require continuous medical care, physical therapy, speech therapy, occupational therapy, and extra stimulation at home to try to compensate for developmental delays. It is a difficult routine for families, especially the mothers, who almost always assume the role of full-time caregiver. \u201cThe mothers of these children devote themselves to their care 24 hours a day, which can lead to fatigue and friction in relationships with husbands and other children,\u201d says pediatric ophthalmologist Liana Ventura, coauthor of the study published in JAMA Network Open<\/em> and chair of the Altino Ventura Foundation\u2019s board of trustees.<\/p>\n

At 2.5 years of age, many children with Congenital Zika Syndrome (CZS) are comparable to babies of just a few months<\/p><\/blockquote>\n

Together with ophthalmologist Camila Ventura, head of scientific research at the foundation, Liana and her colleagues have already published 70 scientific articles describing the damage Zika causes to the eyes and the brain structures responsible for vision. Most children with CZS have moderate or severe visual impairment due to brain damage. Half of those with microcephaly also have eye injuries.<\/p>\n

In collaboration with a group led by Andrea Zin of the renowned Fernandes Figueira Institute (IFF) at the Oswaldo Cruz Foundation (FIOCRUZ) in Rio de Janeiro, a team led by Dora Fix Ventura, a psychologist from the University of S\u00e3o Paulo (USP) identified an even higher proportion of eye problems. Of the 44 children seen by the IFF, 29 had lesions in the internal structures of their eyes and 24 had such low visual acuity that they can be classified as legally blind.<\/p>\n

The geographic regions most affected by the virus and with the most cases of CZS are areas with greater social inequality, higher levels of poverty, and fewer specialist health services, usually in state capitals. Despite this fact, the public health system plays an important role in responding to the needs of these children, although much work is left to philanthropic institutions. Caring for children with the syndrome has a high financial impact on the families.<\/p>\n

Economist M\u00e1rcia Pinto from IFF surveyed 95 caregivers of children with severe forms of CZS. Eight out of 10 belonged to lower-middle and lower economic classes. In order to take care of their child, 54% had stopped working (another 27% were already unemployed beforehand). Half of them spent 40% of the family\u2019s income on care for the child with CZS. One of the biggest expenses was travel\u2014most of the children receive treatment at three different health centers according to the study, published in Cadernos de Sa\u00fade P\u00fablica <\/em>last November. Federal legislation passed in 2019 ensures lifetime benefits equal to the monthly minimum wage\u2014currently R$1,212\u2014for children with CZS. \u201cThis benefit barely covers the child\u2019s expenses\u2014they often need special foods, diapers, and medicines not always available through the public system. And there is still the rest of the family to take care of,\u201d says the economist. \u201cThese families need social and financial protection.\u201d<\/p>\n

In several Brazilian states, women like Inabela have organized groups with other mothers on social media to exchange experiences on how to care for their children and demand access to treatment and other rights for them. \u201cThese mothers do everything they can to secure the care and medication their children need,\u201d says pediatrician Maria Elisabeth Moreira, coordinator of a team at IFF that has taken care of more than 500 children with CZS and is currently caring for 146. \u201cThey are true warriors.\u201d<\/p>\n

The mystery of why cases were so high in the Northeast<\/strong><\/p>\n

The Zika virus epidemic that hit Brazil in 2015 and 2016 was curiously concentrated in one region. Between 50% and 84% of suspected cases of Congenital Zika Syndrome (CZS) occurred in the Northeast, where less than a third of the country’s population lives. Studies have tested six plausible hypotheses, but a consensus is yet to be reached on which is the most likely or to what extent each contributes.<\/p>\n

\u201cThe problem most likely results from a combination of genetic and environmental factors,\u201d suggests Stevens Rehen, a neuroscientist from the Federal University of Rio de Janeiro (UFRJ) and the D’Or Institute of Research and Teaching (IDOR).<\/p>\n

Specific DNA changes may play a role in who the syndrome affects. Children with CZS have genetic variations that make the neural progenitor cells responsible for generating different types of brain cells more susceptible to the virus. A group led by geneticist Mayana Zatz of the University of S\u00e3o Paulo (USP) collected skin cells from pairs of twins where one had the syndrome the other did not, and stimulated them to become neural progenitors. In the children with CZS, the progenitors were more easily infected and developed less. This propensity was determined by a set of genes, according to the study published in Nature Communications<\/em> in 2018.<\/p>\n

A lack of protein in the mother\u2019s diet may also have contributed. At UFRJ, a team led by neuroscientist Patricia Garcez subjected pregnant mice to a low-protein diet and infected them with the virus. The experiment resulted in changes to the placenta and fetal development problems, with a reduction in the formation of central nervous system cells. The data was presented in Science Advances <\/em>in 2020,<\/em> showing that the offspring had smaller brains.<\/p>\n

Another study carried out at UFRJ by Rehen and his colleagues showed that exposure to saxitoxin\u2014a substance produced by cyanobacteria and found in greater concentration in water reservoirs in the Northeast\u2014doubled neural progenitor death rates in human minibrains infected by Zika. When administered to pregnant mice infected with the virus, the toxin led to the birth of offspring with brain abnormalities. The study was published in PLOS Neglected Tropical Diseases <\/em>in 2020.<\/p>\n

Albert Ko, an epidemiologist from the Yale School of Public Health and FIOCRUZ in Bahia, is investigating another environmental factor: the greater number of mosquitoes infected with the virus in poor areas of the Northeast, something that would increase the probability of transmission to pregnant women. The reason for his suspicion? In a study published in Science<\/em> in 2019, his team found that 73% of people in a poor region of Salvador had been infected in a very short period of time. \u201cAreas with heavy infestation showed higher rates of transmission,\u201d he says.<\/p>\n

There is also the contested possibility that previous infection with the dengue virus, which is common in the Northeast, exacerbates the damage caused by Zika. Antibodies produced to fight dengue may also provide partial immunity against Zika. But instead of offering protection against the virus, this flawed immunity helps it invade cells and multiply, worsening the infection, as observed in 2019 by Ko and by Michel Nussenzveig, from the Rockefeller University, USA.<\/p>\n

Maur\u00edcio Nogueira, a virologist from the S\u00e3o Jos\u00e9 do Rio Preto School of Medicine (FAMERP), and his colleagues compared the effects of Zika infection on pregnant women in two cities: Rio de Janeiro, where mosquito infestation and occurrences of CZS were both high, and Manaus, where the problem was rarer. The study, published in Virus<\/em> in 2021, showed that the syndrome was more common among children of mothers infected in the first trimester of pregnancy.<\/div>\n

Scientific articles
\n<\/strong>SCHULER-FACCINI, L.\u00a0et al<\/em>.\u00a0Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects<\/a>.\u00a0Frontiers in Genetics<\/strong>. 8 mar. 2022.
\nTAKAHASI, E. M.\u00a0et al<\/em>.\u00a0Gross motor function in children with Congenital Zika Syndrome<\/a>.\u00a0Neuropediatrics<\/strong>. v. 52, n. 1, p. 34-43. feb. 2021.
\nDIAS, T. K. C.\u00a0et al<\/em>.\u00a0First aid intervention with mothers\/caregivers of children affected by the Zika virus in Brazil<\/a>.\u00a0Applied Nursing Research<\/strong>. v. 57, 15135. feb. 2021.
\nPAIX\u00c3O, E. S.\u00a0et al<\/em>.\u00a0Mortality from Congenital Zika Syndrome \u2013 Nationwide cohort study in Brazil<\/a>.\u00a0New England Journal of Medicine<\/strong>. v. 386, n. 8, p. 757-67. 24 feb. 2022.
\nCARVALHO, A.\u00a0et al<\/em>.\u00a0Clinical and neurodevelopmental features in children with cerebral palsy and probable congenital Zika<\/a>.\u00a0Brain & Development<\/strong>. v. 41, n. 7, p. 587-94. aug. 2019.
\nWHEELER, A. C.\u00a0et al<\/em>.\u00a0Developmental outcomes among young children with Congenital Zika Syndrome in Brazil<\/a>.\u00a0Jama Network Open. v. 3, n. 5, e204096. 5 may. 2020.
\nAGUILAR TICONA, J. P.\u00a0et al<\/em>.\u00a0Heterogeneous development of children with Congenital Zika Syndrome-associated microcephaly<\/a>.\u00a0PLOS ONE<\/strong><\/em>. v. 16, n. 9, e0256444. 15 sep. 2021.
\nVENTURA, C. V.\u00a0et al<\/em>.\u00a0Zika: Neurological and ocular findings in infant without microcephaly<\/a>.\u00a0The Lancet<\/strong>. v. 387, n. 10037, p. 2502. 18 jun. 2016.
\nVENTURA, L. O.\u00a0et al<\/em>.\u00a0Visual impairment evaluation in 119 children with Congenital Zika Syndrome<\/a>.\u00a0Journal of the American Association Pediatric Ophthalmology and Strabismus<\/strong>. v. 22, n. 3, p. 218-22. 12 apr. 2018.
\nVENTURA, C. V.\u00a0et al<\/em>.\u00a0Ophthalmological manifestations in Congenital Zika Syndrome in 469 Brazilian children<\/a>.\u00a0Journal of the American Association Pediatric Ophthalmology and Strabismus<\/strong>. Jun. 2021.
\nPINTO, M.\u00a0et al<\/em>.\u00a0Gasto catastr\u00f3fico na s\u00edndrome cong\u00eanita do v\u00edrus Zika: resultados de um estudo transversal com cuidadores de crian\u00e7as no Rio de Janeiro, Brasil<\/a>.\u00a0Cadernos de Sa\u00fade P\u00fablica<\/strong>. v. 37, n. 11. 22 nov. 2021.
\nCAIRES-JUNIOR, L. C.\u00a0et al<\/em>.\u00a0Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells<\/a>.\u00a0Nature Communications<\/strong>. v. 9, 475. 2 feb. 2018.
\nBARBEITO-ANDR\u00c9S, J.\u00a0et al<\/em>.\u00a0Congenital Zika syndrome is associated with maternal protein malnutrition<\/a>.\u00a0Science Advances<\/strong>. v. 6, n. 2. 10 jan. 2020.
\nPEDROSA, C. S. G.\u00a0et al<\/em>.\u00a0The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus<\/a>.\u00a0PLOS Neglected Tropical Diseases<\/strong>. v. 14, n. 3, e0008060. 12 mar. 2020.
\nRODRIGUEZ-BARRAQUER, I.\u00a0et al<\/em>.\u00a0Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region<\/a>.\u00a0Science<\/strong>. v. 363, n. 6427, p. 607-10. 8 feb. 2019.
\nROBBIANI, D. F.\u00a0et al<\/em>.\u00a0Risk of Zika microcephaly correlates with features of maternal antibodies<\/a>.\u00a0Journal of Experimental Medicine<\/strong>. v. 216, n. 10, p. 2302-15. 14 aug. 2019.
\nDAMASCENO, L.\u00a0et al<\/em>.\u00a0Why did ZIKV perinatal outcomes differ in distinct regions of Brazil? An exploratory study of two cohorts<\/a>.\u00a0Viruses<\/strong>. v. 13, n. 5, p. 736. 23 apr. 2021.
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