Feeding characteristics and growth among children with prenatal exposure to Zika virus with and without microcephaly in the microcephaly epidemic research group pediatric cohort.

OBJECTIVE: To describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months. DESIGN: Using data from the prospective Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC), children without microcephaly born to mothers with evidence of ZIKV infection during pregnancy (ZIKV-exposed children without microcephaly) and children with Zika-related microcephaly were compared using repeated cross-sectional analyses within the following age strata: birth; 1 to 12; 13 to 24; 25 to 36; and 37 to 48 months. The groups were compared in relation to prematurity, birth weight, breastfeeding, alternative feeding routes, dysphagia and anthropometric profiles based on the World Health Organization Anthro z-scores (weight-length/height, weight-age, length/height-age and BMI-age). RESULTS: The first assessment included 248 children, 77 (31.05%) with microcephaly and 171 (68.95%) without microcephaly. The final assessment was performed on 86 children. Prematurity was 2.35 times higher and low birth weight was 3.49 times higher in children with microcephaly. The frequency of breastfeeding was high (> 80%) in both groups. On discharge from the maternity hospital, the frequency of children requiring alternative feeding route in both groups was less than 5%. After 12 months of age, children with microcephaly required alternative feeding route more often than children without microcephaly. In children with microcephaly, the z-score of all growth indicators was lower than in children without microcephaly. CONCLUSIONS: Children with Zika-related microcephaly were more frequently premature and low birth weight and remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those of the children without microcephaly.

Risk of death following chikungunya virus disease in the 100 Million Brazilian Cohort, 2015-18: a matched cohort study and self-controlled case series.

BACKGROUND: Chikungunya virus outbreaks have been associated with excess deaths at the ecological level. Previous studies have assessed the risk factors for severe versus mild chikungunya virus disease. However, the risk of death following chikungunya virus disease compared with the risk of death in individuals without the disease remains unexplored. We aimed to investigate the risk of death in the 2 years following chikungunya virus disease. METHODS: We used a population-based cohort study and a self-controlled case series to estimate mortality risks associated with chikungunya virus disease between Jan 1, 2015, and Dec 31, 2018, in Brazil. The dataset was created by linking national databases for social programmes, notifiable diseases, and mortality. For the matched cohort design, individuals with chikungunya virus disease recorded between Jan 1, 2015, and Dec 31, 2018, were considered as exposed and those who were arbovirus disease-free and alive during the study period were considered as unexposed. For the self-controlled case series, we included all deaths from individuals with a chikungunya virus disease record, and each individual acted as their own control according to different study periods relative to the date of disease. The primary outcome was all-cause natural mortality up to 728 days after onset of chikungunya virus disease symptoms, and secondary outcomes were cause-specific deaths, including ischaemic heart diseases, diabetes, and cerebrovascular diseases. FINDINGS: In the matched cohort study, we included 143 787 individuals with chikungunya virus disease who were matched, at the day of symptom onset, to unexposed individuals using sociodemographic factors. The incidence rate ratio (IRR) of death within 7 days of chikungunya symptom onset was 8·40 (95% CI 4·83-20·09) as compared with the unexposed group and decreased to 2·26 (1·50-3·77) at 57-84 days and 1·05 (0·82-1·35) at 85-168 days, with IRR close to 1 and wide CI in the subsequent periods. For the secondary outcomes, the IRR of deaths within 28 days after disease onset were: 1·80 (0·58-7·00) for cerebrovascular diseases, 3·75 (1·33-17·00) for diabetes, and 3·67 (1·25-14·00) for ischaemic heart disease, and there was no evidence of increased risk in the subsequent periods. For the self-controlled case series study, 1933 individuals died after having had chikungunya virus disease and were included in the analysis. The IRR of all-cause natural death within 7 days of symptom onset of chikungunya virus disease was 8·75 (7·18-10·66) and decreased to 1·59 (1·26-2·00) at 57-84 days and 1·09 (0·92-1·29) at 85-168 days. For the secondary outcomes, the IRRs of deaths within 28 days after disease onset were: 2·73 (1·50-4·96) for cerebrovascular diseases, 8·43 (5·00-14·21) for diabetes, and 2·38 (1·33-4·26) for ischaemic heart disease, and there was no evidence of increased risk at 85-168 days. INTERPRETATION: Chikungunya virus disease is associated with an increased risk of death for up to 84 days after symptom onset, including deaths from cerebrovascular diseases, ischaemic heart diseases, and diabetes. This study highlights the need for equitable access to approved vaccines and effective anti-chikungunya virus therapeutics and reinforces the importance of robust vector-control efforts to reduce viral transmission. FUNDING: Brazilian National Research Council (CNPq), Fundação de Amparo à Pesquisa do Estado da Bahia, Wellcome Trust, and UK Medical Research Council. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Incidence and risk factors of tuberculosis among 420 854 household contacts of patients with tuberculosis in the 100 Million Brazilian Cohort (2004-18): a cohort study.

BACKGROUND: Although household contacts of patients with tuberculosis are known to be particularly vulnerable to tuberculosis, the published evidence focused on this group at high risk within the low-income and middle-income country context remains sparse. Using nationwide data from Brazil, we aimed to estimate the incidence and investigate the socioeconomic and clinical determinants of tuberculosis in a cohort of contacts of tuberculosis patients. METHODS: In this cohort study, we linked individual socioeconomic and demographic data from the 100 Million Brazilian Cohort to mortality data and tuberculosis registries, identified contacts of tuberculosis index patients diagnosed from Jan 1, 2004 to Dec 31, 2018, and followed up the contacts until the contact's subsequent tuberculosis diagnosis, the contact's death, or Dec 31, 2018. We investigated factors associated with active tuberculosis using multilevel Poisson regressions, allowing for municipality-level and household-level random effects. FINDINGS: We studied 420 854 household contacts of 137 131 tuberculosis index patients. During the 15 years of follow-up (median 4·4 years [IQR 1·9-7·6]), we detected 8953 contacts with tuberculosis. The tuberculosis incidence among contacts was 427·8 per 100 000 person-years at risk (95% CI 419·1-436·8), 16-times higher than the incidence in the general population (26·2 [26·1-26·3]) and the risk was prolonged. Tuberculosis incidence was associated with the index patient being preschool aged (<5 years; adjusted risk ratio 4·15 [95% CI 3·26-5·28]) or having pulmonary tuberculosis (2·84 [2·55-3·17]). INTERPRETATION: The high and sustained risk of tuberculosis among contacts reinforces the need to systematically expand and strengthen contact tracing and preventive treatment policies in Brazil in order to achieve national and international targets for tuberculosis elimination. FUNDING: Wellcome Trust and Brazilian Ministry of Health.

Perinatal health outcomes of international migrant women in Brazil: A nationwide data linkage study of the CIDACS birth cohort (2011-2018).

BACKGROUND: We investigated perinatal outcomes among live births from international migrant and local-born mothers in a cohort of low-income individuals in Brazil. METHODS: We linked nationwide birth registries to mortality records and socioeconomic data from the CIDACS Birth Cohort and studied singleton live births of women aged 10-49 years from 1st January 2011 to 31st December 2018. We used logistic regressions to investigate differences in antenatal care, adverse pregnancy outcomes, and neonatal (i.e., ≤28 days) mortality among international migrants compared to non-migrants in Brazil; and explored the interaction between migration, race/ethnicity and living in international border municipalities. RESULTS: We studied 10,279,011 live births, of which 9469 (0.1 %) were born to international migrants. Migrant women were more likely than their Brazilian-born counterparts to have a previous foetal loss (ORadj: 1.16, 1.11-1.22), a delayed start of antenatal care (i.e., beyond 1st trimester) (1.22, 95%CI:1.16-1.28), a newborn who is large for gestational age (1.29, 1.22-1.36), or a newborn with congenital anomalies (1.37, 1.14-1.65). Conversely, migrant women were less likely to deliver prematurely (0.89, 0.82-0.95) or have a low birth weight infant (0.74, 0.68-0.81). There were no differences in neonatal mortality rates between migrants and non-migrants. Our analyses also showed that, when disparities in perinatal outcomes were present, disparities were mostly concentrated among indigenous mothers in international borders and among live births of Black mothers in non-borders. CONCLUSION: Although live births of international migrants generally have lower rates of adverse birth outcomes, our results suggest that indigenous and Black migrant mothers may face disproportionate barriers to accessing antenatal care.

Municipality-level measles, mumps, and rubella (MMR) vaccine coverage and deprivation in Brazil: A nationwide ecological study, 2006 to 2020.

To better understand the declining rates of routine childhood vaccination in Brazil, we investigated the association between measles, mumps, and rubella (MMR) first dose vaccine coverage and deprivation at the municipality level. Using routinely collected data from 5565 Brazilian municipalities from 2006 to 2020, we investigated the association between municipality-level MMR vaccine first dose coverage (i.e., as a continuous variable and as a percentage of municipalities attaining the 95% target coverage) in relation to quintiles of municipality-level deprivation, measured by the Brazilian Deprivation Index (Índice Brasileiro de Privação, IBP), and geographic regions. From 2006 to 2020, the mean municipality-level MMR vaccine coverage declined across all deprivation quintiles and regions of Brazil, by an average of 1.2% per year. The most deprived quintile of municipalities had higher coverage on average, but also the steepest declines in coverage (i.e., an annual decline of 1.64% versus 0.61% in the least deprived quintile) in the period of 2006-2020, and the largest drop in coverage at the beginning of the COVID-19 pandemic (2019-2020). Across all deprivation quintiles and regions (except for the Southeast region), less than 50% of municipalities in Brazil met the 95% MMR coverage target in 2020.The decrease in MMR first dose vaccine coverage in Brazil is widespread, but steeper declines have been observed in the most deprived municipalities. To promote vaccine equity and prevent future outbreaks, further research is urgently needed to understand the causal mechanisms underlying the observed associations between municipality-level MMR vaccine coverage and deprivation.

Risk of adverse pregnancy and infant outcomes associated with prenatal Zika virus infection: a post-epidemic cohort in Central-West Brazil.

This study aimed to estimate the risks of adverse infant outcomes in the first year of life related to prenatal Zika virus (ZIKV) exposure. A prospective cohort of pregnant women with rash was recruited in Central-West Brazil in a post-epidemic period (January 2017 to April 2019). We evaluated participants' medical histories and performed ZIKV diagnostic testing using molecular (reverse transcription polymerase chain reaction [RT-PCR]) and serologic (immunoglobulin [Ig]M and plaque reduction neutralization tests [PRNT90]) assays. The ZIKV-positive group included both RT-PCR-confirmed cases as well as IgM and/or PRNT90-positive probable cases. Children were evaluated at birth and in the first 12 months of life. Transfontanellar ultrasound, central nervous system computed tomography, eye fundoscopy and retinography were performed. We estimated the absolute risk and 95% confidence interval (95% CI) of adverse infant outcomes among confirmed prenatally ZIKV-exposed children. Among 81 pregnant women with rash, 43 (53.1%) were ZIKV infected. The absolute risk of microcephaly among offspring of ZIKV-infected pregnant women was 7.0% (95% CI: 1.5-19.1), including the two cases of microcephaly detected prenatally and one detected postnatally. In total, 54.5% (95% CI: 39.8-68.7) of children in the ZIKV-exposed group had at least one ophthalmic abnormality, with the most frequent abnormalities being focal pigmentary mottling and chorioretinal atrophy or scarring. Our findings reinforce the importance of long-term monitoring of prenatally ZIKV-exposed children born apparently asymptomatic for Congenital Zika Syndrome.

Mortality among over 6 million internal and international migrants in Brazil: a study using the 100 Million Brazilian Cohort.

Background: To understand if migrants living in poverty in low and middle-income countries (LMICs) have mortality advantages over the non-migrant population, we investigated mortality risk patterns among internal and international migrants in Brazil over their life course. Methods: We linked socio-economic and mortality data from 1st January 2011 to 31st December 2018 in the 100 Million Brazilian Cohort and calculated all-cause and cause-specific age-standardised mortality rates according to individuals' migration status for men and women. Using Cox regression models, we estimated the age- and sex-adjusted mortality hazard ratios (HR) for internal migrants (i.e., Brazilian-born individuals living in a different Brazilian state than their birth) compared to Brazilian-born non-migrants; and for international migrants (i.e., people born in another country) compared to Brazilian-born individuals. Findings: The study followed up 45,051,476 individuals, of whom 6,057,814 were internal migrants, and 277,230 were international migrants. Internal migrants had similar all-cause mortality compared to Brazilian non-migrants (aHR = 0.99, 95% CI = 0.98-0.99), marginally higher mortality for ischaemic heart diseases (aHR = 1.04, 95% CI = 1.03-1.05) and higher for stroke (aHR = 1.11, 95% CI = 1.09-1.13). Compared to Brazilian-born individuals, international migrants had 18% lower all-cause mortality (aHR = 0.82, 95% CI = 0.80-0.84), with up to 50% lower mortality from interpersonal violence among men (aHR = 0.50, 95% CI = 0.40-0.64), but higher mortality from avoidable causes related to maternal health (aHR = 2.17, 95% CI = 1.17-4.05). Interpretation: Although internal migrants had similar all-cause mortality, international migrants had lower all-cause mortality compared to non-migrants. Further investigations using intersectional approaches are warranted to understand the marked variations by migration status, age, and sex for specific causes of death, such as elevated maternal mortality and male lower interpersonal violence-related mortality among international migrants. Funding: The Wellcome Trust.

Causes of death in children with congenital Zika syndrome in Brazil, 2015 to 2018: A nationwide record linkage study.

BACKGROUND: Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018. METHODS AND FINDINGS: In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother's infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother's infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls. CONCLUSION: The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.

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%.

Characterizing Disabilities in Preschool Aged Children with Congenital Zika Virus Syndrome with the ICF Model.

Understanding functioning and disabilities in children with Congenital Zika Syndrome (CZS) is essential for health planning. We describe disabilities present in children with CZS followed in a reference hospital in Rio de Janeiro, Brazil, based on the biopsychosocial model of the International Classification of Functioning, Disability and Health (ICF). This was a cohort study of children >3 years of age with CZS. Disability was characterized through outcomes related to ICF components assessed via clinical and motor development evaluations. Among 50 children, with a median age of 40 months, 47 (94%) presented with severe impairment and 46 (92%) had microcephaly. Damage to the head and neck was found in most children, with abnormal central nervous system imaging universally present. Most children had cognitive impairment (92%), muscle tone problems (90%), and speech deficits (94%). We found movement limitations in all categories but more pervasively (80−94%), in postural transfers and displacements. The main environmental factors identified in the ICF model were the use of products or substances for personal consumption and access to health services. Children with CZS have extremely high rates of disability beyond aged 3 years, particularly regarding motor activity. ICF-based models can contribute to the assessment of health domains.

Cortical Auditory Evoked Potentials in Children with Prenatal Exposure to Zika Virus.

Prenatal exposure to ZIKV can cause neurologic and auditory damage. The electrophysiological responses obtained by Cortical Auditory Evoked Potentials (CAEP) may provide an objective method to investigate the function of cortical auditory pathways in children exposed to ZIKV. This case series analyzed the findings of CAEP in prenatal-period ZIKV-exposed children with and without microcephaly. The CAEP was performed in a total of 24 children. Five magnetic resonance imaging (MRI) images of the inner ear and brain of microcephalic children were analyzed and compared with CAEP measurements. Ventriculomegaly (80%), cortical/subcortical calcification (80%), and brain reduction (60%) were the most common alterations in the MRI. The P1-N1-P2 complex of the CAEP was observed in all children evaluated. The peak N2 was absent in two children. In the comparison of the CAEP measurements between the groups, children with microcephaly presented a higher amplitude of P2 (p = 0.017), which may reflect immaturity of the auditory pathways. Microcephalic and normocephalic children with prenatal exposure to ZIKV presented with the mandatory components of the CAEPs, regardless of changes in the CNS, suggesting that this population has, to some extent, the cortical ability to process sound stimuli preserved.

Characteristics of children of the Microcephaly Epidemic Research Group Pediatric Cohort who developed postnatal microcephaly.

The number of studies published on postnatal microcephaly in children with Congenital Zika Syndrome is small, clinical presentations vary and aspects of the evolution of these children remain unclarified. The present case series examined clinical characteristics and assessed the growth velocity of the head circumference, weight and height Z-scores in 23 children who developed postnatal microcephaly during follow-up in the Microcephaly Epidemic Research Group Pediatric Cohort. To estimate the change in the head circumference, weight and height Z-scores over time and compare the mean difference between sexes, we used multilevel mixed-effects linear regressions with child-specific random effects. Among these children, 60.9% (n = 14/23) presented with craniofacial disproportion, 60.9% (n = 14/23) with strabismus, 47.8% (n = 11/23) with early onset seizures, 47.8% (n = 11/23) with dysphagia and 43.5% (n = 10/23) with arthrogryposis. Of the 82.7% (n = 19/23) children who underwent neuroimaging, 78.9% (n = 15/19) presented with alterations in the central nervous system. Monthly growth velocity, expressed in Z-scores, of the head circumference was - 0.098 (95% CI % - 0.117 to - 0.080), of weight was: - 0.010 (95%-CI - 0.033 to 0.014) and of height was: - 0.023 (95%-CI - 0.046 to 0.0001). Postnatal microcephaly occurred mainly in children who had already presented with signs of severe brain damage at birth; there was variability in weight and height development, with no set pattern.

Socioeconomic risk markers of congenital Zika syndrome: a nationwide, registry-based study in Brazil.

While it is well known that socioeconomic markers are associated with a higher risk of arbovirus infections, research on the relationship between socioeconomic factors and congenital Zika syndrome (CZS) remains limited. This study investigates the relationship between socioeconomic risk markers and live births with CZS in Brazil. We conducted a population-based study using data from all registered live births in Brazil (Live Births Information System) linked with the Public Health Event Record from 1 January 2015 to 31 December 2018. We used logistic regression models to estimate the OR and 95% CIs of CZS based on a three-level framework. In an analysis of 11 366 686 live births, of which 3353 had CZS, we observed that live births of self-identified black or mixed race/brown mothers (1.72 (95% CI 1.47 to 2.01) and 1.37 (95% CI 1.24 to 1.51)) were associated with a higher odds of CZS. Live births from single women compared with married women and those from women with less than 12 years of education compared with those with more than 12 years of education also had higher odds of CZS. In addition, live births following fewer prenatal care appointments had increased odds of CZS in the nationwide data. However, in the analyses conducted in the Northeast region (where the microcephaly epidemic started before the link with Zika virus was established and before preventive measures were known or disseminated), no statistical association was found between the number of prenatal care appointments and the odds of CZS. This study shows that live births of the most socially vulnerable women in Brazil had the greatest odds of CZS. This disproportionate distribution of risk places an even greater burden on already socioeconomically disadvantaged groups, and the lifelong disabilities caused by this syndrome may reinforce existing social and health inequalities.

Dengue, Zika, and Chikungunya viral circulation and hospitalization rates in Brazil from 2014 to 2019: An ecological study.

BACKGROUND: In addition to their direct pathogenic effects, arthropod-borne (arboviruses) have been hypothesized to indirectly contribute to hospitalizations and death through decompensation of pre-existing comorbidities. Using nationwide data routinely collected from 1 January 2014 to 31 December 2019 in Brazil, we investigated whether local increases in arbovirus notifications were associated with excess hospitalization. METHODS: We estimated the relative risks for the association between municipality- and state-level increases in arboviral case notifications and age-standardized hospitalization rates (i.e., classified as direct or indirect based on ICD-10 codes) using Bayesian multilevel models with random effects accounting for temporal and geographic correlations. For municipality-level analyses, we excluded municipalities with <200 notifications of a given arbovirus and further adjusted the models for the local Gini Index, Human Development Index, and Family Healthcare Strategy (Estratégia de Saúde da Família) coverage. Models for dengue, Zika, and chikungunya were performed separately. RESULTS: From 2014 to 2019, Brazil registered 7,566,330 confirmed dengue cases, 159,029 confirmed ZIKV cases, and 433,887 confirmed CHIKV cases. Dengue notifications have an endemic and seasonal pattern, with cases present in 5334 of the 5570 (95.8%) Brazilian municipalities and most (69.5%) registered between February and May. Chikungunya notifications followed a similar seasonal pattern to DENV but with a smaller incidence and were restricted to 4390 (78.8%) municipalities. ZIKV was only notified in 2581 (46.3%) municipalities. Increases in dengue and chikungunya notifications were associated with small increases in age-standardized arbovirus-related hospitalizations, but no consistent association was found with all-cause or other specific indirect causes of hospitalization. Zika was associated to increases in hospitalizations by neurological diseases. CONCLUSIONS: Although we found no clear association between increased incidence of the three arboviruses and excess risks of all-cause or indirect hospitalizations at the municipality- and state-levels, follow-up investigations at the individual-level are warranted to define any potential role of acute arbovirus infection in exacerbating risks of hospitalization from underlying conditions.

Longitudinal Follow-Up of Gross Motor Function in Children with Congenital Zika Virus Syndrome from a Cohort in Rio de Janeiro, Brazil.

Knowledge of how congenital Zika syndrome (CZS) impacts motor development of children longitudinally is important to guide management. The objective of the present study was to describe the evolution of gross motor function in children with CZS in a Rio de Janeiro hospital. In children with CZS without arthrogryposis or other congenital osteoarticular malformations who were followed in a prospective cohort study, motor performance was evaluated at two timepoints using the Gross Motor Function Classification System (GMFCS) and the Gross Motor Function Measurement test (GMFM-88). Among 74 children, at the baseline evaluation, the median age was 13 (8-24) months, and on follow-up, 28 (24-48) months. According to GMFCS at the second timepoint, 6 children were classified as mild, 11 as moderate, and 57 as severe. In the GMFM-88 assessment, children in the severe group had a median score of 10.05 in the baseline evaluation and a follow-up score of 12.40, the moderate group had median scores of 25.60 and 29.60, and the mild group had median scores of 82.60 and 91.00, respectively. Although a small developmental improvement was observed, the motor impairment of children was mainly consistent with severe cerebral palsy. Baseline motor function assessments were predictive of prognosis.

Population-based surveillance for congenital zika virus syndrome: a latent class analysis of recorded cases from 2015-2018.

OBJECTIVE: This study aims to describe clinical findings and determine the medium-term survival of congenital zika syndrome (CZS) suspected cases. METHODS: A retrospective cohort study using routine register-based linked data. It included all suspected cases of CZS born in Brazil from January 1, 2015, to December 31, 2018, and followed up from birth until death, 36 months, or December 31, 2018, whichever came first. Latent class analysis was used to cluster unconfirmed cases into classes with similar combinations of anthropometry at birth, imaging findings, maternally reported rash, region, and year of birth. Kaplan-Meier curves were plotted, and Cox proportional hazards models were fitted to determine mortality up to 36 months. RESULTS: We followed 11,850 suspected cases of CZS, of which 28.3% were confirmed, 9.3% inconclusive and 62.4% unconfirmed. Confirmed cases had almost two times higher mortality when compared with unconfirmed cases. Among unconfirmed cases, we identified three distinct clusters with different mortality trajectories. The highest mortality risk was observed in those with abnormal imaging findings compatible with congenital infections (HR = 12.6; IC95%8.8-18.0) and other abnormalities (HR = 11.6; IC95%8.6-15.6) compared with those with normal imaging findings. The risk was high in those with severe microcephaly (HR = 8.2; IC95%6.4-10.6) and macrocephaly (HR = 6.6; IC95%4.5-9.7) compared with normal head size. CONCLUSION: Abnormal imaging and head circumference appear to be the main drivers of the increased mortality among suspected cases of CZS. We suggest identifying children who are more likely to die and have a greater need to optimise interventions and resource allocation regardless of the final diagnoses.

Co-circulation of Chikungunya Virus during the 2015-2017 Zika Virus Outbreak in Pernambuco, Brazil: An Analysis of the Microcephaly Epidemic Research Group Pregnancy Cohort.

Co-circulation of arthropod-borne viruses, particularly those with shared mosquito vectors like Zika (ZIKV) and Chikungunya (CHIKV), is increasingly reported. An accurate differential diagnosis between ZIKV and CHIKV is of high clinical importance, especially in the context of pregnancy, but remains challenging due to limitations in the availability of specialized laboratory testing facilities. Using data collected from the prospective pregnancy cohort study of the Microcephaly Epidemic Research Group, which followed up pregnant persons with rash during the peak and decline of the 2015-2017 ZIKV epidemic in Recife, Pernambuco, Brazil, this study aims to describe the geographic and temporal distribution of ZIKV and CHIKV infections and to investigate the extent to which ZIKV and CHIKV infections may be clinically differentiable. Between December 2015 and June 2017, we observed evidence of co-circulation with laboratory confirmation of 213 ZIKV mono-infections, 55 CHIKV mono-infections, and 58 sequential ZIKV/CHIKV infections (i.e., cases with evidence of acute ZIKV infection with concomitant serological evidence of recent CHIKV infection). In logistic regressions with adjustment for maternal age, ZIKV mono-infected cases had lower odds than CHIKV mono-infected cases of presenting with arthralgia (aOR, 99% CI: 0.33, 0.15-0.74), arthritis (0.35, 0.14-0.85), fatigue (0.40, 0.17-0.96), and headache (0.44, 0.19-1.90). However, sequential ZIKV/CHIKV infections complicated discrimination, as they did not significantly differ in clinical presentation from CHIKV mono-infections. These findings suggest clinical symptoms alone may be insufficient for differentiating between ZIKV and CHIKV infections during pregnancy and therefore laboratory diagnostics continue to be a valuable tool for tailoring care in the event of arboviral co-circulation.

Mortality from Congenital Zika Syndrome - Nationwide Cohort Study in Brazil.

BACKGROUND: Prenatal exposure to Zika virus has potential teratogenic effects, with a wide spectrum of clinical presentation referred to as congenital Zika syndrome. Data on survival among children with congenital Zika syndrome are limited. METHODS: In this population-based cohort study, we used linked, routinely collected data in Brazil, from January 2015 through December 2018, to estimate mortality among live-born children with congenital Zika syndrome as compared with those without the syndrome. Kaplan-Meier curves and survival models were assessed with adjustment for confounding and with stratification according to gestational age, birth weight, and status of being small for gestational age. RESULTS: A total of 11,481,215 live-born children were followed to 36 months of age. The mortality rate was 52.6 deaths (95% confidence interval [CI], 47.6 to 58.0) per 1000 person-years among live-born children with congenital Zika syndrome, as compared with 5.6 deaths (95% CI, 5.6 to 5.7) per 1000 person-years among those without the syndrome. The mortality rate ratio among live-born children with congenital Zika syndrome, as compared with those without the syndrome, was 11.3 (95% CI, 10.2 to 12.4). Among infants born before 32 weeks of gestation or with a birth weight of less than 1500 g, the risks of death were similar regardless of congenital Zika syndrome status. Among infants born at term, those with congenital Zika syndrome were 14.3 times (95% CI, 12.4 to 16.4) as likely to die as those without the syndrome (mortality rate, 38.4 vs. 2.7 deaths per 1000 person-years). Among infants with a birth weight of 2500 g or greater, those with congenital Zika syndrome were 12.9 times (95% CI, 10.9 to 15.3) as likely to die as those without the syndrome (mortality rate, 32.6 vs. 2.5 deaths per 1000 person-years). The burden of congenital anomalies, diseases of the nervous system, and infectious diseases as recorded causes of deaths was higher among live-born children with congenital Zika syndrome than among those without the syndrome. CONCLUSIONS: The risk of death was higher among live-born children with congenital Zika syndrome than among those without the syndrome and persisted throughout the first 3 years of life. (Funded by the Ministry of Health of Brazil and others.).

Audiological follow-up of children with congenital Zika syndrome.

How does the auditory function of children with congenital Zika syndrome present during the first three years of life? To determine the auditory function of children with congenital Zika syndrome during the first three years of life and estimate the frequency and long-term presentation of hearing loss in this syndrome, an auditory assessment with screening and diagnostic tests was conducted. The screening test consisted of measuring the short latency ABR using click stimuli. If the ABR click indicated hearing loss, confirmation was obtained with a frequency-specific ABR (FS-ABR), in which the stimuli were tone bursts at frequencies of 500 and 2000 Hz by bone and air conduction. This case series included 107 children with confirmed congenital Zika syndrome, and the cumulative incidence of sensorineural hearing loss in the first three years of life was 9.3% (10/107). There were no cases of delayed-onset or progressive deficits in hearing. Early presentation of sensorineural hearing loss seems to occur with a higher frequency in children with congenital Zika syndrome than in the general population. Sensorineural hearing loss resulting from congenital Zika virus infection does not appear to present with delayed onset or with progressive deficits.