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.

Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%.

Early Predictors of Poor Neurologic Outcomes in a Prospective Cohort of Infants With Antenatal Exposure to Zika Virus.

BACKGROUND: Identify early predictors of poor neurodevelopment in infants with antenatal Zika virus (ZIKV) exposure. METHODS: Analysis of a prospective cohort of infants with antenatal ZIKV exposure confirmed by maternal or infant RT-PCR or IgM during the epidemic in Rio de Janeiro, Brazil. Clinical findings before 3 months of age were associated with Bayley-III Scales of Infant and Toddler Development conducted after 6 months of age. RESULTS: ZIKV exposure was confirmed in 219 cases; 162 infants were normocephalic, 53 were microcephalic, 4 had no head circumference recorded because of perinatal death/LTFU. Seven of the 112 normocephalic infants developed secondary microcephaly between 3 weeks and 8 months of age. Among the normocephalic at birth cohort, the mean HCZ among normal, at risk, and developmentally delayed children was significantly different (ANOVA, P = 0.02). In particular, the mean HCZ of the developmentally delayed group was significantly lower than that of the normal group (Tukey's test, P = 0.014). HCZ was more strongly associated with lower expressive language scores (P = 0.04) than receptive language scores (P = 0.06). The rate of auditory abnormalities differed among the normal, at risk, and developmentally delayed groups (Chi-squared test, P = 0.016), which was driven by the significant difference between the normal and at risk groups (post hoc test, P = 0.011, risk ratio 3.94). Auditory abnormalities were associated with both expressive and receptive language delays (P = 0.02 and P = 0.02, respectively). CONCLUSIONS: Clear predictors of neurodevelopment in normocephalic ZIKV-exposed children have not been previously identified. Our findings demonstrate that smaller HCZ and auditory abnormalities in these infants correlate with poor neurodevelopment as toddlers. Language delay is the most prominent developmental concern among these children, who will require frequent auditory and speech evaluations throughout childhood.

Ophthalmological manifestations in congenital Zika syndrome in 469 Brazilian children.

PURPOSE: To analyze the spectrum of ophthalmologic manifestations in a large sample of children with congenital Zika syndrome (CZS) in Brazil. METHODS: The medical records of infants born in the states of Pernambuco, Bahia, and Rio de Janeiro, Brazil, between December 2015 and December 2016 with clinical manifestations of CZS and positive reverse transcription polymerase-chain-reaction (RT-PCR) and/or serology for the Zika virus were reviewed retrospectively. Data were collected from the record of the first ophthalmological assessment, performed on admission. Children with other congenital infectious diseases, genetic conditions, and incomplete medical records were excluded. RESULTS: A total of 469 infants (242 female [51.6%]) were included. Mean age at examination was 5.0 ± 7.1 months (range, 0.0-36.0 months). Of the 469 infants, 197 (42.0%) were from Rio de Janeiro, 144 (30.7%) from Pernambuco, and 128 (27.3%) from Bahia States. Microcephaly at birth was detected in 214 (45.6%) children; 62 cases (29.0%) were severe. Pernambuco had significantly more children born with microcephaly compared with Bahia and Rio de Janeiro (P < 0.001). Ocular manifestations were found in 269 of 938 eyes (28.7%; 148/469 children [31.6%]). The main ocular alterations were optic nerve pallor in 122 of 938 eyes (13.0%), focal pigment mottling in 112 eyes (11.9%), and chorioretinal scars in 101 eyes (10.8%). A higher prevalence of ocular manifestations was seen in Pernambuco (P < 0.001). No microcephaly was observed in 252 of 466 children (54.1%); of these, 19 children (7.5%) had funduscopic findings. CONCLUSIONS: One-third of children with CZS had ocular manifestations. Children from Pernambuco were more affected. Ocular abnormalities were found in 7.5% of children without microcephaly.

Adverse fetal and neonatal outcomes in pregnancies with confirmed Zika Virus infection in Rio de Janeiro, Brazil: A cohort study.

OBJECTIVE: To analyze adverse fetal and neonatal outcomes of Zika virus infection by the timing of infection during pregnancy. Method: Cohort study of 190 pregnancies with 193 offspring with a positive RT-PCR test for Zika virus (March/2016 to April/2017). RESULTS: Death or defects related to congenital Zika virus infection were identified in 37.3% of fetuses and newborns, and microcephaly in 21.4% of the newborns. The proportion of small for gestational age newborns was 21.9%. Maternal symptoms in the first trimester were significantly associated with the birth of newborns with microcephaly/cerebral atrophy, small for gestational age and with the deaths (one abortion, one stillbirth and the two neonatal deaths). Maternal infection during the second trimester was further associated with asymptomatic newborns at birth. The study showed that 58.5% of the offspring with microcephaly and / or cortical atrophy were small for gestational age, with an evident decrease in symptomatic offspring without microcephaly, 24.1%, and with only 9.1% in the asymptomatic group. CONCLUSION: This study showed that the earlier the symptoms appear during gestation, the more severe the endpoints. We found a higher percentage of small for gestational age newborns exposed to Zika virus early in gestation. We also found a group of apparently asymptomatic newborns with proven Zika infection, which highlights the importance of follow up studies in this population.

Association Between Antenatal Exposure to Zika Virus and Anatomical and Neurodevelopmental Abnormalities in Children.

Importance: Zika virus (ZIKV) is a mosquito-borne flavivirus recognized as teratogenic since the 2015 to 2016 epidemic. Antenatal ZIKV exposure causes brain anomalies, yet the full spectrum has not been delineated. Objective: To characterize the clinical features of ZIKV infection at a pediatric referral center in Rio de Janeiro, Brazil, among children with antenatal ZIKV exposure. Design, Setting, and Participants: Retrospective cohort study conducted from May to July 2019 of a prospective cohort of 296 infants with antenatal ZIKV exposure followed up since December 2015 at a tertiary maternity-pediatric hospital. Exposures: Zika virus infection during pregnancy. Main Outcomes and Measures: Characterization of clinical features with anthropometric, neurologic, cardiologic, ophthalmologic, audiometric, and neuroimaging evaluations in infancy and neurodevelopmental assessments (Bayley Scales of Infant and Toddler Development, Third Edition) from 6 to 42 months of age, stratified by head circumference at birth (head circumference within the reference range, or normocephaly [NC] vs microcephaly [MC]). Results: Antenatal exposure to ZIKV was confirmed for 219 of 296 children (74.0%) referred to Instituto Fernandes Figueira with suspected ZIKV infection through positive maternal or neonatal polymerase chain reaction analysis or IgM serology results. Of these children, 110 (50.2%) were boys, ages ranged from 0 to 4 years, and 53 (24.2%) had congenital microcephaly. The anomalies observed in ZIKV-exposed children with MC or NC were failure to thrive (MC: 38 of 53 [71.7%]; NC: 73 of 143 [51.0%]), cardiac malformations (MC: 19 of 46 [41.3%]; NC: 20 of 100 [20.0%]), excess nuchal skin (MC: 16 of 22 [72.7%]; NC: 35 of 93 [37.6%]), auditory abnormalities (MC: 13 of 50 [26.0%]; NC: 14 of 141 [9.9%]), and eye abnormalities (MC: 42 of 53 [79.2%]; NC: 28 of 158 [17.7%]). Although they experienced fewer neurologic abnormalities than children born with MC, those with NC also had frequent neurologic abnormalities (109 of 160 [68.1%]), including hyperreflexia (36 of 136 [26.5%]), abnormal tone (53 of 137 [38.7%]), congenital neuromotor signs (39 of 93 [41.9%]), feeding difficulties (15 of 143 [10.5%]), and abnormal brain imaging results (44 of 150 [29.3%]). Among 112 children with NC with Bayley-III evaluations, 72 (64.3%) had average or above-average scores; 30 (26.8%) scored 1 SD below average in at least 1 domain; and 10 (8.9%) scored 2 SD below average in at least 1 domain. Among 112 children with NC, a smaller head circumference at birth was significantly associated with subsequent below-average cognitive scores (U = 499.5; z = -2.833; P = .004) and language scores (U = 235.5; z = -2.491; P = .01). Conclusions and Relevance: Children without MC who were exposed to ZIKV in utero had a high frequency of anatomical and neurodevelopmental abnormalities. The head circumference at birth for children with NC was associated with neurocognitive development. Recognition of the wide spectrum of clinical phenotypes is critical to ensure early referral to rehabilitative interventions.

Neurodevelopment of children exposed intra-uterus by Zika virus: A case series.

The main goal of this manuscript was to investigate the neurodevelopment of children exposed by Zika virus in the intrauterine period who are asymptomatic at birth. Newborns with documented Zika virus exposure during the intrauterine period who were asymptomatic at birth were followed in the first two years of life for neurodevelopment using Bayley III test. Children were classified as having normal or delayed neurodevelopment for age based on most recent Bayley III evaluation results. Eighty-four infants were included in the study. The first Bayley III evaluation was performed at a mean chronological age of 9.7±3.1 month; 13 children (15%) had a delay in one of the three domains, distributed as follow: 10 (12%) in the language domain and 3 (3.5%) in the motor domain. The most recent Bayley III evaluation was performed at a mean age 15.3±3.1 months; 42 children (50%) had a delay in one of the three domains: 4 (5%) in cognition, 31 (37%) in language, and 20 (24%) in motor performance. There were no statistical differences in Gender, Gestational Age, Birth Weight and Head Circurference at birth between children with normal and delayed neurodevelopment for age. A very high proportion of children exposed ZIKV during pregnancy who were asymptomatic at birth demonstrated a delay in neurodevelopment, mainly in the language domain, the first two years of life.

The association of depression, anxiety, and stress with caring for a child with Congenital Zika Syndrome in Brazil; Results of a cross-sectional study.

BACKGROUND: Zika virus (ZIKV) infection in pregnancy can cause microcephaly and a wide spectrum of severe adverse outcomes, collectively called "Congenital Zika Syndrome" (CZS). Parenting a child with disabilities can have adverse mental health impacts, but these associations have not been fully explored in the context of CZS in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was undertaken in Recife and Rio de Janeiro, including 163 caregivers of a child with CZS (cases) and 324 caregivers with an unaffected child (comparison subjects), identified from existing studies. The primary caregiver, almost always the mother, was interviewed using a structured questionnaire to collect information on: depression, anxiety, and stress (Depression, Anxiety, and Stress Scale-DASS-21), social support (Medical Outcomes Study Social Support Scale-MOS-SSS), and socio-demographic data. Data was collected May 2017-January 2018. Ethical standards were adhered to throughout the research. A high proportion of mothers reported experiencing severe or extremely severe levels of depression (18%), anxiety (27%) and stress (36%). Mothers of children with CZS were more likely to experience symptoms of depression, anxiety andstress, compared to mothers of comparison children. These associations were more apparent among mothers living in Rio de Janeiro. These differences were reduced after adjustment for socio-economic status and social support. Among mothers of children with CZS, low social support was linked to higher levels of depression, anxiety and stress, but there was no association with socio-economic status. CONCLUSIONS/SIGNIFICANCE: Depression, anxiety and stress were very common among mothers of young children in Brazil, regardless of whether they were parenting a child with disabilities. Mothers of children with CZS may be particularly vulnerable to poor mental health, and this association may be buffered through better social support.

Utilização de indicadores de desempenho em um Comitê de Ética em Pesquisa no Rio de Janeiro - Brasil / Utilización de indicadores de desempeño en un Comité de Ética en Investigación en Rio de Janeiro, Brasil / Use of Performance Indicators in a Research Ethics Committee in Rio de Janeiro, Brazil

Resumo: O presente estudo tem como principais objetivos utilizar os indicadores desenvolvidos como ferramenta para avaliar o desempenho do Comitê de Ética em Pesquisa de uma instituição Federal no Rio de Janeiro, quanto à eficiência e eficácia de sua operação, e determinar os motivos que fazem com que a duração do processo de aprovação dos projetos analisados exceda a meta de 60 dias. Com base em uma revisão da literatura foram desenvolvidos indicadores para avaliar os processos do CEP usando um modelo de estrutura-processo-resultado. Para observar tendências nos indicadores avaliados, foram extraídos e analisados os dados relacionados a todos os protocolos submetidos ao CEP entre janeiro de 2009 e dezembro de 2014. O comitê de ética do presente estudo utilizou indicadores para identificar os pontos críticos dos seus processos e assim melhorar seu desempenho.

Resumen: El presente estudio tiene como principales objetivos utilizar los indicadores desarrollados como herramienta para evaluar el desempeño del Comité de Ética en Investigación de una institución Federal en Rio de Janeiro, en cuanto a la eficiencia y eficacia de su operación, y determinar los motivos que hacen que la duración del proceso de aprobación de los proyectos analizados exceda la meta de 60 días. Con base en una revisión de la literatura fueron desarrollados indicadores para evaluar los procesos del CEI usando un modelo de estructura-proceso-resultado. Para observar tendencias en los indicadores evaluados, fueron extraídos y analizados los datos relacionados a todos los protocolos sometidos al CEI entre enero de 2009 y diciembre de 2014. El comité de ética del presente estudio utilizó indicadores para identificar los puntos críticos de sus procesos y, así, mejorar su desempeño.

Abstract: The main objective of this study is to use the indicators developed as a tool to evaluate the performance of the Research Ethics Committee of a Federal institution in Rio de Janeiro, regarding the efficiency and effectiveness of its operation, and determine the reasons that make that the length of the approval process of the analyzed projects exceeds the 60-day goal. Based on a review of the literature, indicators were developed to evaluate the processes of the RES using a structure-process-result model. To observe trends in the indicators evaluated, the data related to all the protocols submitted to the RES between January 2009 and December 2014 were extracted and analyzed. The ethics committee of the present study used indicators to identify the critical points of its processes in order to improve its performance.

Visual function in infants with antenatal Zika virus exposure.

PURPOSE: To report the findings of a cross-sectional study of visual function in infants with confirmed or suspected antenatal Zika virus (ZIKV) infection seen at a single referral center in Rio de Janeiro. METHODS: Infants were examined following the ZIKV outbreak period at Instituto Fernandes Figueira/FIOCRUZ. Visual function was considered abnormal if an infant could not fix and follow a standardized high-contrast target (10 cm) by 3-6 months of age. Visual function and associations with structural eye abnormalities, central nervous system (CNS) abnormalities, microcephaly, and nystagmus were assessed. Sensitivity and specificity of screening criteria for structural eye abnormalities was assessed. RESULTS: A total of 173 infants met inclusion criteria. Abnormal visual function was found in 52 infants (30.0%) and was significantly associated with eye abnormalities (40/52; OR = 44.2; 95% CI, 16.6-117.6), CNS abnormalities (50/52; OR = 64.0; 95% CI, 14.7-277.6), microcephaly (44/52; OR = 31.5; 95% CI, 12.7-77.8), and nystagmus (26/52; OR = 120.0; 95% CI, 15.6-924.5). Using microcephaly as screening criteria for the detection of eye abnormalities provided a sensitivity of 88.9% (95% CI, 76.0-96.3) and specificity of 82.8% (95% CI, 75.1-88.9). Using both abnormal visual function and microcephaly increased sensitivity to 100% (95% CI, 92.1-100.0) and decreased specificity to 80.5% (95% CI, 72.5-86.9). CONCLUSIONS: Infants with suspected antenatal ZIKV infection and reduced visual function should be referred to an ophthalmologist. Visual function assessments are helpful in screening for antenatal ZIKV exposure in resource-limited settings and can identify infants who may benefit from visual habilitation.

Prevalence of IgG Autoantibodies against GD3 Ganglioside in Acute Zika Virus Infection.

Zika virus (ZIKV) disease has become a global health emergency with devastating effects on public health. Recent evidences implicate the virus as an emergent neuropathological agent promoting serious pathologies of the human nervous system, that include destructive and malformation consequences such as development of ocular and fetal brain lesions, microcephaly in neonates, and Guillain-Barré syndrome (GBS) in adults. These neurological disorders of both central and peripheral nervous systems are thought to be associated to the neurotropic properties of the virus that has ability to infect neural stem cells as well as peripheral neurons, a hallmark of its pathogenicity. The presence of autoantibodies against gangliosides plays a pivotal role in the etiogenesis of GBS and a variety of neurological disorders. Gangliosides are a class of galactose-containing cerebrosides mainly expressed in nervous system tissues playing a critical role in the physiology of neural cells and neurogenesis. Herein, our findings indicate that patients at acute phase of ZIKV infection without any neurological signs show increased levels of IgG autoantibody against GD3 gangliosides, a class of glycolipid found to be highly expressed in neural stem cell acting in the maintenance of their self-renewal cellular capacity. It is possible that a pathological threshold of these antibodies is only acquired in secondary or subsequent infections. In the light of these evidences, we propose that the target of GD3 by autoimmune responses may possibly has an effect in the neuropathy and neurogenesis disorder seen during ZIKV infection.

Persistence of Zika Virus After Birth: Clinical, Virological, Neuroimaging, and Neuropathological Documentation in a 5-Month Infant With Congenital Zika Syndrome.

During the Zika epidemic in Brazil, a baby was born at term with microcephaly and arthrogryposis. The mother had Zika symptoms at 10 weeks of gestation. At 17 weeks, ultrasound showed cerebral malformation and ventriculomegaly. At 24 weeks, the amniotic fluid contained ZIKV RNA and at birth, placenta and maternal blood were also positive using RT-qPCR. At birth the baby urine contained ZIKV RNA, whereas CSF at birth and urine at 17 days did not. Seizures started at 6 days. EEG was abnormal and CT scan showed cerebral atrophy, calcifications, lissencephaly, ventriculomegaly, and cerebellar hypoplasia. Bacterial sepsis at 2 months was treated. A sudden increase in head circumference occurred at 4 months necessitating ventricle-peritoneal shunt placement. At 5 months, the infant died with sepsis due to bacterial meningitis. Neuropathological findings were as severe as some of those found in neonates who died soon after birth, including hydrocephalus, destructive lesions/calcification, gliosis, abnormal neuronal migration, dysmaturation of nerve cells, hypomyelination, loss of descending axons, and spinal motor neurons. ZIKV RNA was detected only in frozen brain tissue using RT-qPCR, but infected cells were not detected by in situ hybridization. Progressive gliosis and microgliosis in the midbrain may have contributed to aqueduct compression and subsequent hydrocephalus. The etiology of progressive disease after in utero infection is not clear and requires investigation.

Educating neonatal nurses in Brazil: a before-and-after study with interrupted time series analysis.

BACKGROUND: Preterm birth contributes significantly to infant mortality and morbidity, including blindness from retinopathy of prematurity (ROP). Access to intensive neonatal care is expanding in many countries, but care is not always optimal, one factor being that nursing is often by inadequately trained nurse assistants. OBJECTIVE: The aim of this study was to evaluate whether an educational package for nurses improves a range of outcomes including survival rates and severe ROP in 5 neonatal units in Rio de Janeiro, Brazil. METHODS: The study design included an uncontrolled before-and-after study in 5 units, with interrupted time series analysis. Participatory approaches were used to develop a self-administered educational package for control of pain, oxygenation, infection, nutrition, and temperature and to improve supportive care ('POINTS of Care'). Educational materials and DVD clips were developed and training skills of nurse tutors were enhanced. There were two 1-year periods of data collection before and after a 3-month period of self-administration of the education package. RESULTS: Overall, 74% of 401 nurses and nurse assistants were trained. A total of 679 and 563 infants were included in the pre- and post-training periods, respectively. Despite improvement in knowledge and nursing practices, such as the delivery and monitoring of oxygen, there was no change in survival (pre-training 80%, post-training 78.2%), severe ROP (1.6 vs. 2.8%), sepsis (11.3 vs. 12.3 cases per 1,000 infant days) or other outcomes. Outcomes worsened over the pre-intervention period but the change to an improvement after the intervention was not statistically significant. During the study period many trained staff left the units, but few were replaced. CONCLUSIONS: Future studies need to focus on barriers to implementation, team building, leadership and governance, as well as the acquisition of knowledge and skills.

Development of a technique for evaluating temporal parameters of sucking in breastfeeding preterm newborns.

AIMS: The aim of the current study was to developed and test the reliability of a technique for measuring temporal parameters of sucking in breastfeeding infants. METHODS: The technique was developed using a cohort of 11 term and 12 preterm infants, and subsequently evaluated using a cohort of 43 preterm infants. Measurements related to sucking pressure in the term and preterm infants were acquired. The signals were recorded for 5 min, saved on a computer, and stored for analysis. For purposes of analysis, the minute with the highest quality signal was chosen. Signal analysis was performed by two researchers, and inter- and intra-observer agreement was assessed. The newborns in the sample had different gestational ages. RESULTS: A technique was developed for the analysis of temporal parameters of sucking during breastfeeding and evaluated in 43 preterm infants with different gestational ages for the following variables: number of bursts per minute, number of sucks per burst, sucking rate, pause rate, and duration of pauses. The intra-observer agreement was 0.85 and the inter-observer agreement was 0.85. CONCLUSIONS: The technique that was developed and validated proved capable of measuring temporal parameters of sucking in breastfeeding newborns.