Fetal, neonatal, and infant outcomes associated with maternal Zika virus infection during pregnancy: A systematic review and meta-analysis.

The occurrence of fetal and neonatal disorders in pregnant women with Zika virus infection in the literature is not consistent. This study aims to estimate the prevalence rate of these disorders in fetuses/neonates of pregnant women with confirmed or probable infection by Zika virus. A systematic review with meta-analysis was conducted in November 2020. Cohort studies that contained primary data on the prevalence of unfavorable outcomes in fetuses or neonates of women with confirmed or probable Zika virus infection during pregnancy were included. A total of 21 cohort studies were included, with a total of 35,568 pregnant women. The meta-analysis showed that central nervous system abnormalities had the highest prevalence ratio of 0.06 (95% CI 0.03-0.09). Intracranial calcifications had a prevalence ratio of 0.01 (95% CI 0.01-0.02), and ventriculomegaly 0.01 (95% CI 0.01-0.02). The prevalence ratio of microcephaly was 0.03 (95% CI 0.02-0.05), fetal loss (miscarriage and stillbirth) was 0.04 (95% CI 0.02-0.06), Small for Gestational Age was 0.04 (95% CI 0.00-0,09), Low Birth Weight was 0.05 (95% CI 0.03-0.08) and Prematurity was 0.07 (95% CI 0.04-0.10). The positivity in RT-PCR for ZIKV performed in neonates born to infected mothers during pregnancy was 0.25 (95% CI 0.06-0.44). We also performed the meta-analysis of meta-analysis for microcephaly with the prevalence ratios from other two previously systematic reviews: 0.03 (95% CI 0.00-0.25). Our results contribute to measuring the impact of Zika virus infection during pregnancy on children's health. The continuous knowledge of this magnitude is essential for the implementation development of health initiatives and programs, in addition to promoting disease prevention, especially in the development of a vaccine for Zika virus. PROSPERO protocol registration: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019125543.

Case Report: Multiorgan Involvement with Congenital Zika Syndrome.

We report the case of an infant born with congenital Zika syndrome (CZS). During the largest Zika virus (ZIKV) outbreak in Peru, the mother presented with fever and rash that were confirmed to be due to ZIKV by real-time PCR. The infant was born with severe microcephaly. Imaging revealed corpus callosum dysgenesis, lissencephaly, ventriculomegaly, and calcifications. Mild hypertrophic cardiomyopathy with diastolic dysfunction was reported in the echocardiogram. Valgus deviation of the lower extremities and a left clubfoot were diagnosed at birth. The hip ultrasound showed incipient signs of Graf type II dysplasia. The findings confirm that CZS is a multiorgan phenotype in which microcephaly is merely the tip of the iceberg. A multidisciplinary approach is needed for the evaluation of these children.

[Congenital Zika syndrome in Argentina: case series study]. / Síndrome de Zika congénito en la Argentina: presentación de dos casos clínicos.

In 2015, there was an increase in the incidence of congenital microcephaly in newborns in Brazil. Months later, the causal relationship between Zika virus and these findings was discovered. In Argentina, during the first outbreak there were 5 cases of congenital Zika syndrome reported. In 2017, there was a new outbreak which involved Salta province. We describe 2 patients with autochthonous congenital Zika syndrome: one of the babies with severe congenital microcephaly with lissencephaly, calcifications and ventriculomegaly; and another baby with postnatal microcephaly with asymmetric polymicrogyria, calcifications and delayed myelination. The real impact of this disease is still uncertain, so it is necessary an adequate multidisciplinary monitoring of patients exposed to Zika virus to better understand the infection and its natural history.

En 2015, se observó un incremento en la incidencia de microcefalia congénita en recién nacidos en Brasil. Meses más tarde, se descubrió la relación causal entre el virus del Zika y estos hallazgos. Durante el primer brote en la Argentina, se reportaron 5 casos de síndrome de Zika congénito. En 2017, hubo un nuevo brote que involucró la provincia de Salta. En este trabajo, se presentan 2 casos clínicos con síndrome de Zika congénito autóctonos: una paciente con microcefalia congénita grave con lisencefalia, calcificaciones corticosubcorticales y ventriculomegalia y otra paciente con microcefalia posnatal con polimicrogiria asimétrica y calcificaciones subcorticales y retraso en la mielinización. El real impacto de esta enfermedad aún es incierto; es necesario un adecuado seguimiento multidisciplinario de los pacientes expuestos al virus del Zika para comprender mejor la infección y su historia natural.

Updated Imaging Findings in Congenital Zika Syndrome: A Disease Story That is Still Being Written.

In congenital Zika virus syndrome (CZS), the most frequent radiological findings are calcifications in the cortical-white matter junction and malformations of cortical development (pachygyria or polymicrogyria, which occur predominantly in the frontal lobes, or a simplified gyral pattern), ventriculomegaly, enlargement of the cisterna magna and the extra-axial subarachnoid space, corpus callosum abnormalities, and reduced brain volume. This syndrome can also result in a decrease in the brainstem and cerebellum volumes and delayed myelination. Infants with CZS may show venous thrombosis and lenticulostriate vasculopathies. Over a 3-year follow-up period, many infants with CZS showed hydrocephalus, reduction in brain calcifications, and greater reduction in brain thickness.

Neuroimaging findings using transfontanellar ultrasound in newborns with microcephaly: a possible association with congenital Zika virus infection.

OBJECTIVE: The objective of this study is to determine the main neuroimaging findings of microcephalic newborns with possible Zika virus (ZIKV) intrauterine infection using transfontanellar cranial ultrasound. METHODS: We performed a retrospective study to describe the main neuroimaging findings in newborns with microcephaly and possible association with congenital ZIKV infection. Microcephaly was defined in the postnatal period using transfontanellar cranial examination which was performed using both two- (2D) and three-dimensional (3D) ultrasound. RESULTS: One hundred and fifty newborns with microcephaly were identified during the study period. The mean ± (standard deviation - SD) of cephalic perimeter was 28.5 ± 4.2 cm (range, 25-38 cm). Transfontanellar neuroimaging patterns detected cerebral calcifications, neuronal migrational abnormalities, dysgenesis of the corpus callosum, and cerebellar atrophy in 34.9%, 31.1%, 26%, and 16.2%, respectively. Hydrocephalus was seen in 28% of overall newborns. A history of maculopapular rash was present in almost half of the mothers (46.1%). CONCLUSION: Neuroimaging patterns by means of transfontanellar ultrasound are accurate and diagnostic investigations of brain pathology in newborns affected by microcephaly and possible intrauterine ZIKV infection.

Case report: microcephaly associated with Zika virus infection, Colombia.

BACKGROUND: Recently there has been a large outbreak of Zika virus infections in Colombia, South America. The epidemic began in September 2015 and continued to April 2017, for the total number of Zika cases reported of 107,870. For those confirmed Zika cases, there were nearly 20,000 (18.5%) suspected to be pregnant women, resulting in 157 confirmed cases of microcephaly in newborns reported by their health government agency. There is a clear under-estimation of the total number of cases and in addition no prior publications have been published to demonstrate the clinical aspects of the Zika infection in Colombia. We characterized one Zika presentation to be able to compare and contrast with other cases of Zika infection already reported in the literature. CASE PRESENTATION: In this case report, we demonstrate congenital microcephaly at week 19 of gestation in a 34-year-old mother who showed symptoms compatible with Zika virus infection from Sincelejo, State of Sucre, in the Colombian Caribbean. Zika virus RNA was detected in the placenta using real-time reverse transcriptase polymerase chain reaction (RT-PCR). At week 25, the fetus weigh estimate was 770 g, had a cephalic perimeter of 20.2 cm (5th percentile), ventriculomegaly on the right side and dilatation of the fourth ventricle. At week 32, the microcephaly was confirmed with a cephalic perimeter of 22 cm, dilatation of the posterior atrium to 13 mm, an abnormally small cerebellum (29 mm), and an augmented cisterna magna. At birth (39 weeks by cesarean section), the head circumference was 27.5 cm, and computerized axial tomography (Siemens Corp, 32-slides) confirmed microcephaly with calcifications. CONCLUSION: We report a first case of maternal Zika virus infection associated with fetal microcephaly in Colombia and confirmed similar presentation to those observed previous in Brazil, 2015-2016.

Zika infection and the development of neurological defects.

Starting with the outbreak in Brazil, Zika virus (ZIKV) infection has been correlated with severe syndromes such as congenital Zika syndrome and Guillain-Barré syndrome. Here, we review the status of Zika virus pathogenesis in the central nervous system (CNS). One of the main concerns about ZIKV exposure during pregnancy is abnormal brain development, which results in microcephaly in newborns. Recent advances in in vitro research show that ZIKV can infect and obliterate cells from the CNS, such as progenitors, neurons, and glial cells. Neural progenitor cells seem to be the main target of the virus, with infection leading to less cell migration, neurogenesis impairment, cell death and, consequently, microcephaly in newborns. The downsizing of the brain can be directly associated with defective development of the cortical layer. In addition, in vivo investigations in mice reveal that ZIKV can cross the placenta and migrate to fetuses, but with a significant neurotropism, which results in brain damage for the pups. Another finding shows that hydrocephaly is an additional consequence of ZIKV infection, being detected during embryonic and fetal development in mouse, as well as after birth in humans. In spite of the advances in ZIKV research in the last year, the mechanisms underlying ZIKV infection in the CNS require further investigation particularly as there are currently no treatments or vaccines against ZIKV infection.

Zika virus detected in amniotic fluid and umbilical cord blood in an in vitro fertilization-conceived pregnancy in Venezuela.

OBJECTIVE: To describe the consequences of Zika virus infection at 10 weeks of gestation in an IVF-conceived pregnancy in Venezuela. DESIGN: A case report. SETTING: Private assisted reproduction unit. PATIENT(S): A 36-year-old patient who conceived her first pregnancy through IVF and became infected with Zika virus at 10 weeks' gestation in Venezuela. INTERVENTION(S): In vitro fertilization with fresh ET. Clinical, laboratory, and imaging Zika diagnostic methods. MAIN OUTCOME MEASURE(S): Zika virus detection by real-time polymerase chain reaction (PCR) in maternal plasma, PCR in amniotic fluid and umbilical cord blood. Ultrasonography findings of anatomic abnormalities. RESULT(S): Zika infection was confirmed at 10 weeks' gestation by real-time PCR; ultrasound results appeared normal. At 19 weeks' gestation, an ultrasound revealed biometry on three SDs below the means for all parameters but with no apparent anatomic abnormality. Zika virus was positive in maternal urine and amniotic fluid by PCR at 19 weeks' gestation. Ultrasound at 21 weeks + 4 days of gestation showed fetal cerebellar hypoplasia with ventricular dysmorphia, particularly marked on the left, consistent with microcephaly and ventriculomegaly. Because of the poor prognosis, pregnancy was interrupted at 24 weeks' gestation, in France. The PCR in umbilical cord blood taken in this procedure was positive for Zika virus. CONCLUSION(S): Initial ultrasound findings in pregnancy may not be informative. Only at 21 weeks + 4 days of gestation did an ultrasound reveal fetal microcephaly and ventriculomegaly. Combined clinical, laboratory, and imaging findings provided a complete picture of the severe damage caused by Zika infection.

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study.

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.

[Cerebrospinal fluid shunt malfunction not associated with ventricular enlargement. A case report and literature review]. / Disfunktsiya shunta tserebrospinal'noi zhidkosti bez rasshireniya zheludochkov mozga. Sluchai iz praktiki i obzor literatury.

Substantiation of the shunt failure diagnosis and subsequent consideration of indications for surgical elimination of the malfunction is a laborious and challenging process. Identification of a malfunction in doubtful cases requires, in addition to standard examinations, extra diagnostic procedures, which may delay making a decision for several weeks to several months. The article describes a case of mechanical CSF shunt malfunction (breakage and failure of a peritoneal catheter in a 7-year-old girl) with intracranial hypertension symptoms, but without typical enlargement of the brain ventricles. According to the medical history, congenital hydrocephalus in the child was accompanied by an inflammatory process of bacterial and viral etiology. The absence of brain ventricle enlargement was shown not to exclude a probability of shunt malfunction. In this case, a specific phenomenon, an intraparenchymatous cerebrospinal fluid "lake" surrounding a ventricular catheter, was observed. Shunting recovery did not lead to a significant reduction in the phenomenon size. Causes underlying this phenomenon require further investigation.

Zika virus: A rapidly emerging infectious disease.

Zika virus is a flavivirus transmitted to humans via the bite of infected mosquitoes. A recent outbreak in Brazil has spread to several surrounding countries, and the virus also has been reported in the United States. The virus is associated with microcephaly among newborns whose mothers were infected. Because no vaccine or treatment is available, efforts have focused on preventing mosquito bites and advising pregnant women and women trying to get pregnant to avoid active areas of Zika virus transmission. Clinicians should understand the infection, its diagnosis and testing, and monitor pregnant women for travel history to outbreak regions and for the presence of clinical symptoms. Patient education on preventive measures offers the best option to avoid Zika virus infection.

In vitro and in vivo growth alter the population dynamic and properties of a Jeryl Lynn mumps vaccine.

Mumps vaccines are live attenuated viruses. They are known to vary in effectiveness, degree of attenuation and adverse event profile. However, the underlying reasons are poorly understood. We studied two closely related mumps vaccines which originate from the same attenuated Jeryl Lynn-5 strain but have different efficacies. Jeryl Lynn-Canine Kidney (JL-CK), produced on primary canine kidney cells, is less effective than RIT4385, which is produced on chicken embryo fibroblasts. JL-CK and RIT4385 could be distinguished by a number of in vitro and in vivo properties. JL-CK produced heterogeneous, generally smaller plaques than RIT4385, but gave 100-fold higher titres when grown in cells and showed a higher degree of hydrocephalus formation in neonatal rat brains. Sanger sequencing of JL-CK identified 14 regions of heterogeneity throughout the genome. Plaque purification of JL-CK demonstrated the presence of five different Jeryl Lynn-5 variants encompassing the 14 mutations. One JL-CK mutation was associated with a small plaque phenotype, the effects of the others in vitro or in vivo were less clear. Only 4% of the JL-CK population corresponded to the parental Jeryl Lynn-5 strain. Next generation sequencing of JL-CK and virus before and after growth in cell lines or neonatal rat brains showed that propagation in vitro or in vivo altered the population dramatically. Our findings indicate that growth of JL-CK in primary canine kidney cells resulted in the selection of a mixture of mumps virus variants that have different biological properties compared to the parent Jeryl Lynn-5 virus. We also report three previously unknown heterogenic regions within the N gene of the RIT4385 vaccine.

Glycan engagement dictates hydrocephalus induction by serotype 1 reovirus.

UNLABELLED: Receptors expressed on the host cell surface adhere viruses to target cells and serve as determinants of viral tropism. Several viruses bind cell surface glycans to facilitate entry, but the contribution of specific glycan moieties to viral disease is incompletely understood. Reovirus provides a tractable experimental model for studies of viral neuropathogenesis. In newborn mice, serotype 1 (T1) reovirus causes hydrocephalus, whereas serotype 3 (T3) reovirus causes encephalitis. T1 and T3 reoviruses engage distinct glycans, suggesting that glycan-binding capacity contributes to these differences in pathogenesis. Using structure-guided mutagenesis, we engineered a mutant T1 reovirus incapable of binding the T1 reovirus-specific glycan receptor, GM2. The mutant virus induced substantially less hydrocephalus than wild-type virus, an effect phenocopied by wild-type virus infection of GM2-deficient mice. In comparison to wild-type virus, yields of mutant virus were diminished in cultured ependymal cells, the cell type that lines the brain ventricles. These findings suggest that GM2 engagement targets reovirus to ependymal cells in mice and illuminate the function of glycan engagement in reovirus serotype-dependent disease. IMPORTANCE: Receptor utilization strongly influences viral disease, often dictating host range and target cell selection. Different reovirus serotypes bind to different glycans, but a precise function for these molecules in pathogenesis is unknown. We used type 1 (T1) reovirus deficient in binding the GM2 glycan and mice lacking GM2 to pinpoint a role for glycan engagement in hydrocephalus caused by T1 reovirus. This work indicates that engagement of a specific glycan can lead to infection of specific cells in the host and consequent disease at that site. Since reovirus is being developed as a vaccine vector and oncolytic agent, understanding reovirus-glycan interactions may allow manipulation of reovirus glycan-binding properties for therapeutic applications.

The utility of infection screening in isolated mild ventriculomegaly: an observational retrospective study on 141 fetuses.

OBJECTIVE: The aim of this study was to evaluate the utility of screening for infections in case of isolated mild ventriculomegaly (imVM). METHODS: We retrospectively reviewed 141 cases of imVM. Screening for infections including TORCH, parvovirus B19, and syphilis was carried out in all cases. Follow-up ultrasound, fetal karyotype, and magnetic resonance imaging (MRI) were offered. Postnatal follow-up was obtained from pediatricians, medical records, parents, and postmortem reports in cases of termination of pregnancy or stillbirth. RESULTS: The imVM was bilateral in 70 fetuses and unilateral in 71 and regressed during pregnancy in 66.6% of cases. Associated anomalies were observed in 15 cases with follow-up ultrasound and in seven cases with MRI. Fetal karyotype was abnormal in one fetus (47, XXY). Maternal IgM for parvovirus B19 resulted positive in 4.6% of cases, and one neonate was infected without any fetal/neonatal adverse consequence. Recent cytomegalovirus infection was documented in 4.4% of cases. Only in one case the infection was transmitted to the fetus; after 3 years, the child has good neuromotor development but has severe hearing impairment. CONCLUSIONS: When this diagnosis occurs, tests could be limited to cytomegalovirus and parvovirus B19, whereas a complete TORCH screening is probably not necessary.

Acute hydrocephalus in a child with a third ventricle arachnoid cyst and coincidental enteroviral meningitis.

We present a 2.5-year-old child suffering from acute hydrocephalus. First, the child was diagnosed with aseptic viral meningitis. The PCR of the cerebrospinal fluid (CSF) was positive for enterovirus. Subsequently, MRI revealed that the hydrocephalus was caused by a cyst in the third ventricle. During ventriculoscopy, the cyst had all aspects of an arachnoid cyst. An endoscopic fenestration and partial removal of the cyst was performed, combined with a ventriculocisternostomy. The coincidental finding of viral meningitis and a third ventricle arachnoid cyst in a patient with acute hydrocephalus has, to our knowledge, not been described in literature before. If there is a relation between the enteroviral meningitis, the arachnoid cyst (possibly causing a pre-existing subclinical hydrocephalus) and the rapidly evolving neurological deterioration, remains speculative. Proposed mechanisms, by which the viral meningitis could accelerate the disease process, are slight brain swelling or increased CSF production. This rare combination of diagnoses could also be coincidental.

A pilot study using residual newborn dried blood spots to assess the potential role of cytomegalovirus and Toxoplasma gondii in the etiology of congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus. METHODS: Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs). RESULTS: Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99). CONCLUSIONS: Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.

[Congenital cytomegaly in one twin - a case report]. / Wrodzona cytomegalia w ciazy blizniaczej-opis przypadka.

A report on dichorionic/diamniotic pregnancy in which only one, female, fetus was infected with cytomegalovirus and presented with severe congenital diseases at birth. Infection of the fetus occurred after recurrent maternal infection. The second, male, fetus did not have CMV infection. The cesarean section was performed at the 38th week of gestation. The birth weight of the infected girl was 1680g, the main symptoms, beside dystrophy, concerned the central nervous system: microcephaly, brain atrophy, hydrocephalus, corpus callosum agenesis. She also had Turner syndrome symptoms. The viral load was highest in the urine 81.2 x10^6/ml, in the cerebro-spinal fluid 15.4x10^6/ml and lower in blood 0.38 x10^5/ml. The concentration of specific IgG was 308 U/ml. Specific IgM was not detected. Throughout hospitalization, the infection maintained only one viral genotype gB2. Despite treatment with ganciclovir (10 weeks) and foscarnet (2 weeks), the girl died at the age of 8 months. Novel molecular diagnostic techniques (nested and real time PCR) confirmed the congenital infection and were helpful in the monitoring of the infection and treatment efficacy.