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.

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.

Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value (p = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities (p = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika.

The Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC): A Cohort Profile.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG-PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG-PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case-Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a 'task force' of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children's characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia; cryptorchidism and its surgical findings; endocrine dysfunction; and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil.

Zika-related adverse outcomes in a cohort of pregnant women with rash in Pernambuco, Brazil.

BACKGROUND: While Zika virus (ZIKV) is now widely recognized as a teratogen, the frequency and full spectrum of adverse outcomes of congenital ZIKV infection remains incompletely understood. METHODS: Participants in the MERG cohort of pregnant women with rash, recruited from the surveillance system from December/2015-June/2017. Exposure definition was based on a combination of longitudinal data from molecular, serologic (IgM and IgG3) and plaque reduction neutralization tests for ZIKV. Children were evaluated by a team of clinical specialists and by transfontanelle ultrasound and were classified as having microcephaly and/or other signs/symptoms consistent with congenital Zika syndrome (CZS). Risks of adverse outcomes were quantified according to the relative evidence of a ZIKV infection in pregnancy. FINDINGS: 376 women had confirmed and suspected exposure to ZIKV. Among evaluable children born to these mothers, 20% presented with an adverse outcome compatible with exposure to ZIKV during pregnancy. The absolute risk of microcephaly was 2.9% (11/376), of calcifications and/or ventriculomegaly was 7.2% (13/180), of additional neurologic alterations was 5.3% (13/245), of ophthalmologic abnormalities was 7% (15/214), and of dysphagia was 1.8% (4/226). Less than 1% of the children experienced abnormalities across all of the domains simultaneously. Interpretation: Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination. Due to the rare nature of some outcomes and the possibility of later manifestations, large scale individual participant data meta-analysis and the long-term evaluation of children are imperative to identify the full spectrum of this syndrome and to plan actions to reduce damages.

Comparison of Oropharyngeal Dysphagia in Brazilian Children with Prenatal Exposure to Zika Virus, With and Without Microcephaly.

Severe brain damage associated with Zika-related microcephaly (ZRM) have been reported to result in oropharyngeal dysphagia (OPD); however, it is unknown if OPD presents in children with prenatal Zika virus (ZIKV) exposure but only mild or undetectable abnormalities. The aims of this study were: to compare the frequency and characteristics of OPD in children with ZRM and in children without microcephaly born to mothers who tested polymerase chain reaction positive (PCR+) for ZIKV during pregnancy; and to investigate the concordance of caregiver reports of OPD with the diagnosis from the clinical swallowing assessment (CSA). Between Mar/2017 and May/2018, we evaluated 116 children (n = 58 with microcephaly, n = 58 children without microcephaly born to ZIKV PCR + mothers) participating in the Microcephaly Epidemic Research Group (MERG) cohort of children born during the 2015-2016 ZIKV epidemic in Pernambuco, Brazil. To assess OPD we used: a CSA; a clinical assessment of the stomatognathic system; and a questionnaire administered to caregivers. The frequency of OPD was markedly higher in children with ZRM (79.3%) than in the exposed but normocephalic group (8.6%). The children with microcephaly also presented more frequently with anatomic and functional abnormalities in the stomatognathic system. There was a high degree of agreement between the caregiver reports of OPD and the CSA (κ = 0.92). In conclusion, our findings confirm that OPD is a feature of Congenital Zika Syndrome that primarily occurs in children with microcephaly and provide support for policies in which children are referred for rehabilitation with an OPD diagnosis based on caregiver report.

Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil.

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common-and clinically important-endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.

Dental development in children born to Zikv-infected mothers: a case-based study.

BACKGROUND: In Brazil, in October 2015, an outbreak of Zika virus (ZIKV) infection and an increase in newborns with microcephaly suggested a relationship between maternal infection and microcephaly in children. OBJECTIVE: First, to assess the presence of dental bud sin 13 infants with a confirmed diagnosis of congenital ZIKV syndrome, born to mothers infected with the virus during pregnancy; second, to evaluate the dental development of these children at a 36-month follow-up. DESIGN: Case-based longitudinal study. RESULTS: Dental radiographs in the first semester showed that all children had dental buds. Along with the study, the individuals presented with various dental disturbances. At the end of the evaluation period, some children still had incomplete deciduous dentition. CONCLUSION: The abnormal chronology of dental eruption and dental development disturbances in children with microcephaly infected with ZIKV born to infected mothers indicate a possible role of the virus in odontogenesis.

Discordant clinical outcomes of congenital Zika virus infection in twin pregnancies.

Congenital Zika syndrome is an emergent cause of a congenital infectious disorder, resulting in severe damage to the central nervous system and microcephaly. Despite advances in understanding the pathophysiology of the disease, we still do not know all the mechanisms enrolled in the vertical transmission of the virus. As has already been reported in other types of congenital infectious disorders in dizygotic twin pregnancies, it is possible that the virus affects only one of the fetuses. In this article, we report on two cases of twin pregnancies exposed to the Zika virus, but with only one of the fetuses affected with microcephaly and brain damage. This indicates the urgent need for more studies regarding the pathophysiology of viral infection and the mechanisms involved in the natural protection against the virus.

Discordant clinical outcomes of congenital Zika virus infection in twin pregnancies / Evolução clínica discordante da infecção congénita do vírus Zika em gestação gemelar

ABSTRACT Congenital Zika syndrome is an emergent cause of a congenital infectious disorder, resulting in severe damage to the central nervous system and microcephaly. Despite advances in understanding the pathophysiology of the disease, we still do not know all the mechanisms enrolled in the vertical transmission of the virus. As has already been reported in other types of congenital infectious disorders in dizygotic twin pregnancies, it is possible that the virus affects only one of the fetuses. In this article, we report on two cases of twin pregnancies exposed to the Zika virus, but with only one of the fetuses affected with microcephaly and brain damage. This indicates the urgent need for more studies regarding the pathophysiology of viral infection and the mechanisms involved in the natural protection against the virus.

RESUMO A síndrome congênita do Zika vírus é uma causa de infecção congênita emergente, resultando em graves danos ao sistema nervoso central e microcefalia. Apesar dos avanços na compreensão da fisiopatologia da doença, ainda não conhecemos todo o mecanismo envolvido na transmissão vertical do vírus. Como já foi relatado em outros tipos de infecções congênitas em gestações gemelares dizigóticas, é possível que apenas um dos fetos seja afetado pelo vírus. Este artigo descreve 2 casos de gestações gemelares expostas ao vírus Zika, onde apenas um dos fetos foi afetado, com microcefalia associado a graves danos no sistema nervoso central. Isso indica a necessidade urgente de mais estudos sobre a fisiopatologia da infecção viral e os mecanismo envolvidos na proteção natural contra o vírus.

Sleep EEG patterns in infants with congenital Zika virus syndrome.

OBJECTIVES: To describe sleep EEG patterns of neonates, and infants with microcephaly due to congenital Zika virus (ZikV) syndrome. METHODS: A descriptive case series of EEGs performed in a cohort of neonates with microcephaly monitored from October 2015 to February 2016 at a University Hospital in Northeast Brazil. Infants were investigated following an established protocol that includes EEG, neuroimaging studies, PCR and specific antibodies for ZikV detection. RESULTS: EEGs (n=37) from 37 infants were reviewed. Age at investigation varied from 1 to 5months (mean=2.6). Diffuse low voltage (n=7), background asymmetry (n=6) and modified hypsarrhythmia with or without burst-suppression (n=11), were the main background abnormalities identified. Interictal EEG abnormalities were identified in 23 recordings (62%) and localized as focal frontal (n=8) or occipital (n=2) spikes/sharp, multifocal spikes/sharp waves (n=13). Electrographic seizures without clinical manifestation were identified in 4 recordings and characterized as focal pseudo rhythmic pattern. Further findings were focal high amplitude slow waves that were registered in the frontal (n=3) or occipital (n=1) regions. CONCLUSIONS: Different types of EEG abnormalities were encountered with a predominance of interictal epileptogenic activity and hypsarrhythmia. SIGNIFICANCE: Sleep EEGs in congenital Zika virus syndrome are consistently abnormal even in infants who have not yet developed epilepsy.

Description of 13 Infants Born During October 2015-January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth - Brazil.

Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).

Congenital Zika syndrome with arthrogryposis: retrospective case series study.

OBJECTIVE: To describe the clinical, radiological, and electromyographic features in a series of children with joint contractures (arthrogryposis) associated with congenital infection presumably caused by Zika virus. DESIGN: Retrospective case series study. SETTING: Association for Assistance of Disabled Children, Pernambuco state, Brazil. PARTICIPANTS: Seven children with arthrogryposis and a diagnosis of congenital infection presumably caused by Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Main clinical, radiological, and electromyographic findings, and likely correlation between clinical and primary neurological abnormalities. RESULTS: The brain images of all seven children were characteristic of congenital infection and arthrogryposis. Two children tested positive for IgM to Zika virus in the cerebrospinal fluid. Arthrogryposis was present in the arms and legs of six children (86%) and the legs of one child (14%). Hip radiographs showed bilateral dislocation in seven children, subluxation of the knee associated with genu valgus in three children (43%), which was bilateral in two (29%). All the children underwent high definition ultrasonography of the joints, and there was no evidence of abnormalities. Moderate signs of remodeling of the motor units and a reduced recruitment pattern were found on needle electromyography (monopolar). Five of the children underwent brain computed tomography (CT) and magnetic resonance imaging (MRI) and the remaining two CT only. All presented malformations of cortical development, calcifications predominantly in the cortex and subcortical white matter (especially in the junction between the cortex and white matter), reduction in brain volume, ventriculomegaly, and hypoplasia of the brainstem and cerebellum. MRI of the spine in four children showed apparent thinning of the cord and reduced ventral roots. CONCLUSIONS: Congenital Zika syndrome should be added to the differential diagnosis of congenital infections and arthrogryposis. The arthrogryposis was unrelated to the abnormalities of the joints themselves, but was possibly of neurogenic origin, with chronic involvement of central and peripheral motor neurones leading to deformities as a result of fixed postures in utero. Based on the neurophysiological observations, we suggest two possible mechanisms: tropism of neurones, with involvement of peripheral and central motor neurones, or a relation with vascular disorders.

Initial Description of the Presumed Congenital Zika Syndrome.

OBJECTIVES: To provide an initial description of the congenital syndrome presumably associated with infection by Zika virus compared with other syndromes including congenital infections of established etiologies. METHODS: We provide an overview of a published case series of 35 cases, a clinical series of 104 cases, and published and unpublished reports of clinical and laboratory findings describing cases diagnosed since the beginning of the epidemic of microcephaly in Brazil. RESULTS: About 60% to 70% of mothers report rash during pregnancy; mainly in the first trimester. Principal features are microcephaly, facial disproportionality, cutis girata, hypertonia/spasticity, hyperreflexia, and irritability; abnormal neuroimages include calcifications, ventriculomegaly, and lissencephaly. Hearing and visual abnormalities may be present. CONCLUSIONS: Preliminary data suggest that severe congenital abnormalities are linked to Zika virus infection. Cases have severe abnormalities, and although sharing many characteristics with congenital abnormalities associated with other viral infections, abnormalities presumably linked to the Zika virus may have distinguishing characteristics. These severe neurologic abnormalities may result in marked mental retardation and motor disabilities for many surviving offspring. POLICY IMPLICATIONS: Affected nations need to prepare to provide complex and costly multidisciplinary care that children diagnosed with this new congenital syndrome will require.

Vitamin D Deficiency in HIV-Infected Women on Antiretroviral Therapy Living in the Tropics.

The effects of HIV/AIDS and antiretroviral drugs on vitamin D metabolism are still mostly unknown. This was a cross-sectional study to estimate the prevalence of vitamin D deficiency and identify its association with the clinical and metabolic parameters among 214 HIV-positive female patients on antiretroviral therapy (ART) in Brazil. The prevalence of vitamin D deficiency (< 30 ng/ml) was 40.65% (87/214). Hypercholesterolemia, high LDL-c, duration of use of current antiretroviral regimen, hypertriglyceridemia, body mass index, age, hypertension, time with AIDS ≥ 10 years and hyperglycemia were selected for multivariate analysis (p < 0.20). After this analysis, hypercholesterolemia and use of current antiretroviral regimen ≥ 3 years remained independently associated with vitamin D deficiency. There was an inverse statistically significant correlation between total cholesterol and serum 25(OH)D levels. High prevalence of vitamin D deficiency was found among HIV-positive women on ART and was independently associated with its prolonged use and with hypercholesterolemia.

Hemiparesia ipsilateral ao angioma em Síndrome de Sturge-Weber / Ipsilateral hemiparesis to the nevus in Sturge-Weber Syndrome

É descrito o caso de uma paciente do sexo feminino, 12 anos com alterações características da Síndrome de Sturge-Weber (nevus angiomatoso, cefaléia e retardo mental). No caso em estudo, há, no entanto, hemiparesia espástica trofomotora ipsilateral ao angioma, ausência de calcificações intracranianas e sinais sequelares de acidente vascular cerebral, achados não usuais nessa síndrome