Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice.

The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and -intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals.

Prenatal disorders and congenital Zika syndrome in squirrel monkeys.

During the Zika virus (ZIKV) outbreak in Brazil (2015-2016), the clinical manifestations associated with its infection were complex and included miscarriage and congenital malformations, not previously described. In this study, we evaluated the prenatal conditions of pregnant female squirrel monkeys (Saimiri collinsi) infected during different gestational thirds (GTs) and assessed all clinical aspects, diagnostic imaging, viremia and the immune response. In our study, 75% of the infected animals in the 1st GT group had significant clinical manifestations, such as miscarriage and prolonged viremia associated with a late immune response. Consequently, their neonates showed fetal neuropathology, such as cerebral hemorrhage, lissencephaly or malformations of the brain grooves, ventriculomegaly, and craniofacial malformations. Thus, our study demonstrated the relevance of pregnant squirrel monkeys as a model for the study of ZIKV infection in neonates due to the broad clinical manifestations presented, including the typical congenital Zika syndrome manifestations described in humans.

Two different prenatal imaging cerebral patterns of tubulinopathy.

To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

Neonatal diabetes is caused by single gene mutations reducing pancreatic ß cell number or impairing ß cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in ß cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human ß cell models (YIPF5 silencing in EndoC-ßH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects ß cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and ß cell failure. Partial YIPF5 silencing in EndoC-ßH1 cells and a patient mutation in stem cells increased the ß cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in ß cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

Prenatal diagnosis of fetal microhydranencephaly: a case report and literature review.

BACKGROUND: The prenatal diagnosis of microhydranencephaly is important and needs to be distinguished from anencephaly, because unlike anencephaly, fetuses with microhydranencephaly can survive after birth. Herein, we report a case of microhydranencephaly that was diagnosed and distinguished from anencephaly prenatally. CASE PRESENTATION: The patient was an 18-year-old woman, 2 gravida nullipara, who presented at 15 weeks of gestation. Ultrasonography showed a normal biparietal diameter (BPD) and no major anomalies. At 23 weeks of gestation, an ultrasound examination revealed a BPD of 40 mm (-5.3 standard deviation, SD). At 29 weeks, anencephaly was suspected despite difficulty in visually examining the fetal head above the orbit. At 34 weeks, insertion of a metreurynter made it possible to observe the skull. Three-dimensional computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the presence of the fetal skull, a prominent occipital bone, sloping forehead, marked microcephaly, cerebral loss, and excess cerebrospinal fluid. This allowed differentiation between microhydranencephaly and anencephaly. She delivered vaginally at 37 weeks, and the child had a birth weight of 2342 g and a head circumference of 24 cm (-5.4 SD). The baby's head was flat above the forehead, with a suspected partial head defect. The baby received desmopressin acetate due to central diabetes insipidus 6 months after birth. CONCLUSIONS: The use of multiple imaging modalities and physical manipulation of the fetal head are required to accurately differentiate between microhydranencephaly and anencephaly.

Role of microglia in the dissemination of Zika virus from mother to fetal brain.

Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects.

Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome.

Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier. Here, we report the characterizations of Mfsd7c-KO mice and compare these characterizations to phenotypic findings in humans with biallelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late-gestation lethality, likely due to CNS phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c-KO embryos was inhibited in cortical ventricular zones and ganglionic eminences. Vascular tips were dilated and fused, resulting in glomeruloid vessels. Nonetheless, CNS blood vessels were intact, without hemorrhage. Both embryos and humans with biallelic FLVCR2 mutations exhibited reduced cerebral cortical layers, enlargement of the cerebral ventricles, and microcephaly. Transcriptomic analysis of Mfsd7cK-KO embryonic brains revealed upregulation of genes involved in glycolysis and angiogenesis. The Mfsd7c-KO brain exhibited hypoxia and neuronal cell death. Our results indicate that MFSD7c is required for the normal growth of CNS blood vessels and that ablation of this gene results in microcephaly-associated vasculopathy in mice and humans.

Effect of head circumference in combination with facial profile line on ultrasonic diagnosis of microcephaly.

Objective: Recently, microcephaly has usually been misdiagnosed only by ultrasound via measurement of head circumference (HC). Therefore, the aim of this study is to find another diagnostic index to supplement the original diagnostic method of microcephaly, to improve the detection rate of fetal microcephaly and to reduce the misdiagnosis rate.Methods: We retrospectively analyzed 123 pregnant women from February 2012 to January 2017 with fetal HC less than two standard deviations (SD). The facial profile line (FPL) was determined by ultrasonography. The first method (M1) was only used HC to determine whether the fetus was microcephaly, the second one (M2) was to combine HC and FPL for the diagnosis of microcephaly. Results were classified into five orderly categories by experienced sonographers. ROC curve was drawn to evaluate the diagnostic effect.Results: Among the pregnant women, 14 cases of fetal head circumference were less than 3SD, 109 were -2SD < HC≤ -3SD. A total of 12 cases were confirmed of microcephaly by magnetic resonance imaging (MRI) or postnatal, 10 cases of HC were less than 3SD, 2 were -2SD < HC≤ -3SD. The area under the ROC curve for M1 and M2 were 0.751 and 0.983 respectively.Conclusion: The HC in combination with FPL can be used to evaluate the fetal HC and forehead development quickly, and to improve the sensitivity and specificity of diagnosing fetal microcephaly.

The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development.

WDR62 mutations that result in protein loss, truncation or single amino-acid substitutions are causative for human microcephaly, indicating critical roles in cell expansion required for brain development. WDR62 missense mutations that retain protein expression represent partial loss-of-function mutants that may therefore provide specific insights into radial glial cell processes critical for brain growth. Here we utilized CRISPR/Cas9 approaches to generate three strains of WDR62 mutant mice; WDR62 V66M/V66M and WDR62R439H/R439H mice recapitulate conserved missense mutations found in humans with microcephaly, with the third strain being a null allele (WDR62stop/stop). Each of these mutations resulted in embryonic lethality to varying degrees and gross morphological defects consistent with ciliopathies (dwarfism, anophthalmia and microcephaly). We find that WDR62 mutant proteins (V66M and R439H) localize to the basal body but fail to recruit CPAP. As a consequence, we observe deficient recruitment of IFT88, a protein that is required for cilia formation. This underpins the maintenance of radial glia as WDR62 mutations caused premature differentiation of radial glia resulting in reduced generation of neurons and cortical thinning. These findings highlight the important role of the primary cilium in neocortical expansion and implicate ciliary dysfunction as underlying the pathology of MCPH2 patients.

Micro-computed tomography as a platform for exploring Drosophila development.

Understanding how events at the molecular and cellular scales contribute to tissue form and function is key to uncovering the mechanisms driving animal development, physiology and disease. Elucidating these mechanisms has been enhanced through the study of model organisms and the use of sophisticated genetic, biochemical and imaging tools. Here, we present an accessible method for non-invasive imaging of Drosophila melanogaster at high resolution using micro-computed tomography (µ-CT). We show how rapid processing of intact animals, at any developmental stage, provides precise quantitative assessment of tissue size and morphology, and permits analysis of inter-organ relationships. We then use µ-CT imaging to study growth defects in the Drosophila brain through the characterization of abnormal spindle (asp) and WD repeat domain 62 (Wdr62), orthologs of the two most commonly mutated genes in human microcephaly patients. Our work demonstrates the power of combining µ-CT with traditional genetic, cellular and developmental biology tools available in model organisms to address novel biological mechanisms that control animal development and disease.

Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System.

In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.

Putative Cellular and Molecular Roles of Zika Virus in Fetal and Pediatric Neuropathologies.

Although the World Health Organization declared an end to the recent Zika virus (ZIKV) outbreak and its association with adverse fetal and pediatric outcome, on November 18, 2016, the virus still remains a severe public health threat. Laboratory experiments thus far supported the suspicions that ZIKV is a teratogenic agent. Evidence indicated that ZIKV infection cripples the host cells' innate immune responses, allowing productive replication and potential dissemination of the virus. In addition, studies suggest potential transplacental passage of the virus and subsequent selective targeting of neural progenitor cells (NPCs). Depletion of NPCs by ZIKV is associated with restricted brain growth. And while microcephaly can result from infection at any gestational stages, the risk is greater during the first trimester. Although a number of recent studies revealed some of specific molecular and cellular roles of ZIKV proteins of this mosquito-borne flavivirus, the mechanisms by which it produces it suspected pathophysiological effects are not completely understood. Thus, this review highlights the cellular and molecular evidence that implicate ZIKV in fetal and pediatric neuropathologies.

[How to deal with a fetal head circumference lower than the third percentile?] / Gestion prénatale des fœtus avec un périmètre crânien inférieur au 3e percentile.

The prenatal finding of a head circumference (HC) below the 3rd percentile (p) remains, in the same way as short femur or increased nuchal translucency with normal karyotype, one the most difficult situations for the praticionner in the setting of prenatal diagnosis. Microcephaly is a gateway to possible cerebral pathologies, but the main objective is to identify serious prenatal situations. A standardized HC measurement, the use of adapted reference tools and charts, longitudinal following of cephalic biometrics in high-risk situations, and systematic central nervous system analysis can increase the diagnostic performance of ultrasound which is often disappointing for microcephaly. The early distinction between associated or isolated microcephaly makes it possible to quickly orient the prenatal management and counseling. Fetal MRI and genetic counseling are fundamental in this context, making it possible to specify at best the etiological diagnosis and to provide assistance to the neuropediatrician in the establishment of an often uncertain prognosis. The recent increase in cases of microcephaly concomitant with the epidemic of the ZIKA virus is an additional argument to improve our practices and the daily apprehension of HC<3rd p.

Zika Virus Infection in Pregnant Women and Microcephaly.

From the discovery of the Zika virus (ZIKV) in 1947 in Uganda (Africa), until its arrival in South America, it was not known that it would affect human reproductive life so severely. Today, damage to the central nervous system is known to be multiple, and microcephaly is considered the tip of the iceberg. Microcephaly actually represents the epilogue of this infection's devastating process on the central nervous system of embryos and fetuses. As a result of central nervous system aggression by the ZIKV, this infection brings the possibility of arthrogryposis, dysphagia, deafness and visual impairment. All of these changes of varying severity directly or indirectly compromise the future life of these children, and are already considered a congenital syndrome linked to the ZIKV. Diagnosis is one of the main difficulties in the approach of this infection. Considering the clinical part, it has manifestations common to infections by the dengue virus and the chikungunya fever, varying only in subjective intensities. The most frequent clinical variables are rash, febrile state, non-purulent conjunctivitis and arthralgia, among others. In terms of laboratory resources, there are also limitations to the subsidiary diagnosis. Molecular biology tests are based on polymerase chain reaction (PCR) with reverse transcriptase (RT) action, since the ZIKV is a ribonucleic acid (RNA) virus. The RT-PCR shows serum or plasma positivity for a short period of time, no more than five days after the onset of the signs and symptoms. The ZIKV urine test is positive for a longer period, up to 14 days. There are still no reliable techniques for the serological diagnosis of this infection. If there are no complications (meningoencephalitis or Guillain-Barré syndrome), further examination is unnecessary to assess systemic impairment. However, evidence is needed to rule out other infections that also cause rashes, such as dengue, chikungunya, syphilis, toxoplasmosis, cytomegalovirus, rubella, and herpes. There is no specific antiviral therapy against ZIKV, and the therapeutic approach to infected pregnant women is limited to the use of antipyretics and analgesics. Anti-inflammatory drugs should be avoided until the diagnosis of dengue is discarded. There is no need to modify the schedule of prenatal visits for pregnant women infected by ZIKV, but it is necessary to guarantee three ultrasound examinations during pregnancy for low-risk pregnancies, and monthly for pregnant women with confirmed ZIKV infection. Vaginal delivery and natural breastfeeding are advised.

Desde a descoberta do vírus Zika (VZIK) em 1947 em Uganda, na África, até sua chegada na América do Sul, não se tinha notícia de que ele seria capaz de comprometer a vida reprodutiva em humanos de forma tão severa. Hoje, sabe-se que os danos sobre o sistema nervoso central são múltiplos, e a microcefalia é considerada a ponta do iceberg, visto que na realidade ela representa o epílogo de um processo devastador desta infecção sobre o sistema nervoso central do embrião e do feto. Em decorrência da agressão do sistema nervoso central pelo VZIK, esta infecção pode provocar artrogripose, disfagia, surdez e comprometimento visual. Todas estas alterações, de gravidade variável, direta ou indiretamente comprometem a vida futura dessas crianças, já sendo considerada uma síndrome congênita ligada ao VZIK. Uma das principais dificuldades na abordagem dessa infecção é relativa ao diagnóstico. Considerando a parte clínica, observa-se que ela apresenta manifestações comuns às infecções pelos vírus da dengue e da febre chikungunya, variando apenas em suas intensidades subjetivas. As variáveis clínicas mais frequentes são o exantema, febrícula, conjuntivite não purulenta e artralgia. No tocante aos recursos laboratoriais, também existem limitações ao diagnóstico subsidiário. As provas de biologia molecular se fundamentam na reação em cadeia da polimerase (RCP) com ação da transcriptase reversa (TT), visto que o VZIK é um vírus ácido ribonucleico (ARN). A TR-RCP apresenta positividade sérica ou plasmática por um período curto de tempo, não ultrapassando cinco dias após início dos sinais e sintomas. Esta pesquisa do VZIK na urina fica positiva por período mais prolongado, chegando a 14 dias. Ainda não existem técnicas seguras para diagnóstico sorológico dessa infecção. Não havendo complicações (meningoencefalite ou síndrome de Guillain-Barré), dificilmente são necessários mais exames complementares para avaliar o comprometimento sistêmico. No entanto, são necessárias provas para descartar as outras infecções que causam exantema, como dengue, chikungunya, sífilis, toxoplasmose, citomegalovírus, rubéola e herpes. Sabe-se que não existe terapia antiviral específica contra o VZIK, e a abordagem terapêutica de gestantes portadoras da infecção limita-se ao uso de antitérmicos e analgésicos. Orienta-se evitar anti-inflamatórios até que o diagnóstico de dengue seja descartado. Sobre a condução do pré-natal, não há necessidade de modificar o cronograma de consultas pré-natais para gestantes que foram infectadas pelo VZIK, mas é necessária a garantia de três exames ecográficos durante a gravidez para gestantes de baixo risco, e mensais para a gestante com infecção confirmada pelo VZIK. A via de parto é vaginal, e está liberado o aleitamento natural.

Diagnostic Accuracy of Ultrasound Scanning for Prenatal Microcephaly in the context of Zika Virus Infection: A Systematic Review and Meta-analysis.

To assess the accuracy of ultrasound measurements of fetal biometric parameters for prenatal diagnosis of microcephaly in the context of Zika virus (ZIKV) infection, we searched bibliographic databases for studies published until March 3rd, 2016. We extracted the numbers of true positives, false positives, true negatives, and false negatives and performed a meta-analysis to estimate group sensitivity and specificity. Predictive values for ZIKV-infected pregnancies were extrapolated from those obtained for pregnancies unrelated to ZIKV. Of 111 eligible full texts, nine studies met our inclusion criteria. Pooled estimates from two studies showed that at 3, 4 and 5 standard deviations (SDs)

Zika Virus Infection in Pregnant Women and Microcephaly / Infecção do vírus Zika em gestantes e microcefalia

Abstract From the discovery of the Zika virus (ZIKV) in 1947 in Uganda (Africa), until its arrival in South America, it was not known that it would affect human reproductive life so severely. Today, damagetothe central nervous system is known to be multiple, and microcephaly is considered the tip of the iceberg. Microcephaly actually represents the epilogue of this infection's devastating process on the central nervous system of embryos and fetuses. As a result of central nervous system aggression by the ZIKV, this infection brings the possibility of arthrogryposis, dysphagia, deafness and visual impairment. All of these changes of varying severity directly or indirectly compromise the future life of these children, and are already considered a congenital syndrome linked to the ZIKV. Diagnosis is one of the main difficulties in the approach of this infection. Considering the clinical part, it has manifestations common to infections by the dengue virus and the chikungunya fever, varying only in subjective intensities. The most frequent clinical variables are rash, febrile state, non-purulent conjunctivitis and arthralgia, among others. In terms of laboratory resources, there are also limitations to the subsidiary diagnosis. Molecular biology tests are based on polymerase chain reaction (PCR)with reverse transcriptase (RT) action, since the ZIKV is a ribonucleic acid (RNA) virus. The RT-PCR shows serum or plasma positivity for a short period of time, no more than five days after the onset of the signs and symptoms. The ZIKVurine test is positive for a longer period, up to 14 days. There are still no reliable techniques for the serological diagnosis of this infection. If there are no complications (meningoencephalitis or Guillain-Barré syndrome), further examination is unnecessary to assess systemic impairment. However, evidence is needed to rule out other infections that also cause rashes, such as dengue, chikungunya, syphilis, toxoplasmosis, cytomegalovirus, rubella, and herpes. There is no specific antiviral therapy against ZIKV, and the therapeutic approach to infected pregnant women is limited to the use of antipyretics and analgesics. Anti-inflammatory drugs should be avoided until the diagnosis of dengue is discarded. There is no need to modify the schedule of prenatal visits for pregnant women infected by ZIKV, but it is necessary to guarantee three ultrasound examinations during pregnancy for low-risk pregnancies, and monthly for pregnant women with confirmed ZIKV infection. Vaginal delivery and natural breastfeeding are advised.

Resumo Desde a descoberta do vírus Zika (VZIK) em 1947 em Uganda, na África, até sua chegada na América do Sul, não se tinha notícia de que ele seria capaz de comprometer a vida reprodutiva emhumanos de forma tão severa.Hoje, sabe-se que os danos sobre o sistema nervoso central são múltiplos, e a microcefalia é considerada a ponta do iceberg, visto que na realidade ela representa o epílogo de um processo devastador desta infecção sobre o sistema nervoso central do embrião e do feto. Em decorrência da agressão do sistema nervoso central pelo VZIK, esta infecção pode provocar artrogripose, disfagia, surdez e comprometimento visual. Todas estas alterações, de gravidade variável, direta ou indiretamente comprometem a vida futura dessas crianças, já sendo considerada uma síndrome congênita ligada aoVZIK. Uma das principais dificuldades na abordagemdessa infecção é relativa ao diagnóstico. Considerando a parte clínica, observa-se que ela apresenta manifestações comuns às infecções pelos vírus da dengue e da febre chikungunya, variando apenasemsuas intensidades subjetivas. As variáveis clínicas mais frequentes são o exantema, febrícula, conjuntivite não purulenta e artralgia. No tocante aos recursos laboratoriais, também existem limitações ao diagnóstico subsidiário. As provas de biologia molecular se fundamentam na reação em cadeia da polimerase (RCP) com ação da transcriptase reversa (TT), visto que o VZIK é umvírus ácido ribonucleico (ARN). ATRRCP apresenta positividade sérica ou plasmática por um período curto de tempo, não ultrapassando cinco dias após início dos sinais e sintomas. Esta pesquisa do VZIK na urina fica positiva por período mais prolongado, chegando a 14 dias. Ainda não existem técnicas seguras para diagnóstico sorológico dessa infecção. Não havendo complicações (meningoencefalite ou síndrome de Guillain-Barré), dificilmente são necessários mais exames complementares para avaliar o comprometimento sistêmico.No entanto, são necessáriasprovaspara descartar as outras infecções que causam exantema, como dengue, chikungunya, sífilis, toxoplasmose, citomegalovírus, rubéola e herpes. Sabe-se que não existe terapia antiviral específica contra o VZIK, e a abordagem terapêutica de gestantes portadoras da infecção limita-se ao uso de antitérmicos e analgésicos. Orienta-se evitar anti-inflamatórios até que o diagnóstico de dengue seja descartado. Sobre a condução do pré-natal, não há necessidade de modificar o cronograma de consultas pré-natais para gestantes que foram infectadas pelo VZIK, mas é necessária a garantia de três exames ecográficos durante a gravidez para gestantes de baixo risco, emensais para a gestante cominfecção confirmada pelo VZIK. Avia de parto é vaginal, e está liberado o aleitamento natural.

Discrepancy in fetal head biometry between ultrasound and MRI in suspected microcephalic fetuses.

Background Microcephaly is one of the most common fetal structural abnormalities, and prenatal microcephaly is considered a group I malformation of cortical development diagnosed according to ultrasound (US) skull measurements. Purpose To evaluate the agreement between fetal head US and magnetic resonance imaging (MRI) biometric measurements of suspected microcephalic fetuses. Material and Methods This institutional review board-approved retrospective study with waived informed consent included 180 pregnant women and was conducted at our medical center from March 2011 to April 2013. Biparietal diameter (BPD) and occipitofrontal diameter (OFD) results of fetal head US normograms were compared to normograms for MRI. We used Pearson and Spearman rho non-parametric correlation coefficients to assess the association between two quantitative variables, paired t-test for paired quantitative variables, and McNemar test for paired qualitative variables. Results The average BPD but not the average OFD percentiles in fetal head US differed significantly from the MRI results ( P < 0.0001). When looking at the accepted microcephaly threshold, both BPD and OFD percentiles differed significantly from MRI ( P < 0.0001 and P < 0.004, respectively). There was no correlation between US-measured skull biometry and MRI-measured brain biometry. Estimated cerebrospinal fluid volumes were significantly lower in the study group compared to 120 fetuses with normal findings in prenatal head US and MRI. Also, we have created a MRI-based normogram of fetal head circumference and gestational age. Conclusion The diagnosis of microcephaly by US alone may be insufficient and ideally should be validated by MRI before a final diagnosis is established.

Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know.

CONTEXT: -The global epidemic of Zika virus (ZIKV) infection has emerged as an important public health problem affecting pregnant women and their infants. OBJECTIVES: -To review the causal association between ZIKV infection during pregnancy and intrauterine fetal infection, microcephaly, brain damage, congenital malformation syndrome, and experimental laboratory models of fetal infection. Many questions remain regarding the risk factors, pathophysiology, epidemiology, and timing of maternal-fetal transmission and disease. These include mechanisms of fetal brain damage and microcephaly; the role of covariables, such as viral burden, duration of viremia, and host genetics, on vertical transmission; and the clinical and pathologic spectrum of congenital Zika syndrome. Additional questions include defining the potential long-term physical and neurobehavioral outcomes for infected infants, whether maternal or fetal host genetics influence the clinical outcome, and whether ZIKV infection can cause maternal morbidity. Finally, are experimental laboratory and animal models of ZIKV infection helpful in addressing maternal-fetal viral transmission and the development of congenital microcephaly? This communication provides current information and attempts to address some of these important questions. DATA SOURCES: -Comprehensive review of published scientific literature. CONCLUSIONS: -Recent advances in epidemiology, clinical medicine, pathology, and experimental studies have provided a great amount of new information regarding vertical ZIKV transmission and the mechanisms of congenital microcephaly, brain damage, and congenital Zika syndrome in a relatively short time. However, much work still needs to be performed to more completely understand the maternal and fetal aspects of this new and emerging viral disease.