Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFNβ and expression of IFN-stimulated genes 48 h after infection. This mouse model provides a platform for identifying factors at the maternal–fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system.
CitationBurd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol 2012; 67: 287-295 doi:10.1111/j.1600-0897.2012 Intrauterine infection and inflammation are known risk factors for brain damage in the neonate irrespective of the gestational age. Infectioninduced maternal immune activation leads to a fetal inflammatory response mediated by cytokines that has been implicated in the development of not only periventricular leukomalacia and cerebral palsy but also a spectrum of neurodevelopmental disorders such as autism and schizophrenia ( Studies involving animal models of maternal inflammation serve a key role in elucidation of mechanisms involved in fetal brain injury associated with exposure to the maternal milieu. These animal models have been shown to result in fetal microglial activation, neurotoxicity as well motor deficits and behavioral abnormalities in the offspring (J Neurosci
Exposure to prenatal inflammation is a known risk factor for long term neurobehavioral disorders including cerebral palsy, schizophrenia, and autism. Models of systemic inflammation during pregnancy have demonstrated an association with an immune response an adverse neurobehavioral outcomes for the exposed fetus. Yet, the most common route for an inflammatory exposure to a fetus is from intrauterine inflammation as occurs with chorioamnionitis. The aims of this study were to assess the effect of intrauterine inflammation on fetal and neonatal brain development and to determine if the gestational age of exposure altered the maternal or fetal response to inflammation. CD‐1 timed pregnant mice on embryonic day 15 (E15) and E18.5 were utilized for this study. Dams were randomized to receive intrauterine infusion of lipopolysaccharide (LPS, 50 μg/dam) or normal saline. Different experimental groups were used to assess both acute and long‐term outcomes. For each gestational age and each treatment group, fetal brains, amniotic fluid, maternal serum and placentas were collected 6 h after intrauterine infusion. Rates of preterm birth, maternal morbidity and litter size were assessed. IL6 levels were assayed in maternal serum and amniotic fluid. An immune response was determined in the fetal brains and placentas by QPCR. Cortical cultures were performed to assess for fetal neuronal injury. Gene expression changes in postnatal day 7 brains from exposed and unexposed pups were determined. In the preterm period, low dose LPS resulted in a 30% preterm birth rate. Litter sizes were not different between the groups at either gestational age. IL6 levels were not significantly increased in maternal serum at either gestational time period. Low dose LPS increased IL6 levels in the amniotic fluid from exposed dams in the term but not preterm period. Regardless of gestational age of exposure, low dose intrauterine LPS activated an immune response in the placenta and fetal brain. Exposure to intrauterine LPS significantly decreased dendritic counts in cortical cultures from both the preterm and term period. Exposure to intrauterine inflammation altered gene expression patterns in the postnatal brain; this effect was dependent on gestational age of exposure. In conclusion, intrauterine inflammation, even in the absence of preterm parturition, can evoke fetal brain injury as evidence by alterations in cytokine expression and neuronal injury. Despite an absent or limited maternal immune response in low dose intrauterine inflammation, the immune system in the placenta is activated which is likely sufficient to induce a fetal immune response and subsequent brain injury. Changes in the fetal brain lead to changes in gene expression patterns into the neonatal period. Subclinical intrauterine inflammation can lead to fetal brain injury and is likely to be mechanistically associated with long term adverse outcomes for exposed offspring.
Adverse neurological outcome is a major cause of long-term morbidity in ex-preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of intrauterine inflammation by intrauterine infusion of lipopolysaccharide (LPS). To investigate the effect of parturition on the immature fetal brain, in the absence of inflammation, we used a non-infectious model of preterm birth by administering RU486. Pro-inflammatory cytokines (IL-10, IL-1β, IL-6 and TNF-α) in amniotic fluid and inflammatory biomarkers in maternal serum and amniotic fluid were compared between the two models using ELISA. Pro-inflammatory cytokine expression was evaluated in the whole fetal brains from the two models. Primary neuronal cultures from the fetal cortex were established from the different models and controls in order to compare the neuronal morphology. Only the intrauterine inflammation model resulted in an elevation of inflammatory biomarkers in the maternal serum and amniotic fluid. Exposure to inflammationinduced preterm birth, but not non-infectious preterm birth, also resulted in an increase in cytokine mRNA in whole fetal brain and in disrupted fetal neuronal morphology. In particular, Microtubuleassociated protein 2 (MAP2) staining was decreased and the number of dendrites was reduced (P < 0.001, ANOVA between groups). These results suggest that inflammation-induced preterm birth and not the process of preterm birth may result in neuroinflammation and alter fetal neuronal morphology. Keywords mouse model of preterm birth; neuroinflammation; neuronal injuryIn the United States, approximately 12% of all live births are delivered preterm (Green et al., 2005). Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity in the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptUnited States. Specifically, PTB is a risk factor for adverse neurological outcome for expreterm children (Anderson and Doyle, 2003;Hack et al., 2005).It has long been believed that cerebral palsy is the primary neurological outcome of clinical interest. However, it is now known that ex-preterm children also are at a significant risk for a spectrum of cognitive and neurobehavioral disorders Wood et al., 2005;Costeloe, 2006;Limperopoulos et al., 2007;Lindstrom et al., 2009) including autism spectrum disorders (Brimacombe et al., 2007;Limperopoulos et al., 2008;Schendel and Bhasin, 2008). Current understanding of the pathogenesis of fetal brain injury in a PTB focuses mainly on specific structural findings of white matter damage (WMD) (Cai et al., 2000;Paintlia et al., 2004;Rousset et al., 2006). This current paradigm may be insufficient to explain the increasing prevalence of adverse cognitive and neurobehavioral outcomes in ex-preterm infants.While adverse neurological outcomes are increasingly prevalent in ex-preterm children, it remains unknown whether th...
Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner.
The first cases of severe pneumonia from a novel coronavirus were reported in Wuhan, China in December 2019. 10 Since then, the virus has been identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection causes fevers, cough, dyspnea, myalgias, pharyngitis, diarrhea, pneumonia, acute respiratory distress syndrome, multisystem organ failure, cytokine storm, endothelial damage, and thrombotic events. 2,3,11-13 It has infected over 12 million people and caused over 550 000 deaths across the globe. 1 The case fatality rate is estimated at 2.3% among the entire population. 14 Recent observations show that the majority of pregnant women are asymptomatic or have mild disease based on the criteria proposed by Wu et al. 14-16 Nevertheless, any infection during pregnancy has potential risks. A recent review of obstetric cases found that 3% of pregnant women with SARS-CoV-2 required intensive care. 17 There have also been cases of preterm labor and perinatal death in the setting of maternal SARS-CoV-2 infection. It is uncertain whether the virus can be vertically transmitted from mother to neonate. Given that SARS-CoV-2 causes inflammatory, coagulation, and endothelial changes, investigating placental and fetal involvement during infection is crucial to providing guidance and care to pregnant patients. Coronaviruses are enveloped positive-sense single-stranded RNA viruses that infect both humans and animals. 18 Human coronaviruses typically cause mild upper and lower respiratory infections, although they can present as severe pneumonia or bronchiolitis. 7,18 Gastrointestinal symptoms can also occur with infection. Coronaviruses were believed to have little clinical significance until the 21st century. Since 2002, three novel coronaviruses have been described: SARS-CoV in 2002, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. SARS-CoV appears to primarily target ciliated epithelial cells via the angiotension-converting enzyme 2 (ACE2) receptor. ACE2 is expressed in the cardiovascular system, gut tissue, adipose tissue, lungs, kidneys, the placenta, and fetal tissue. 19-21 SARS-CoV-2 also binds to ACE2 in order to enter cells. 19,20,22 The clinical presentation of coronaviruses is likely due to both direct cell injury and host response.
Introduction Identification of sexual dysfunction may help physicians diagnose problems such as diabetes, pituitary tumors, atherosclerosis, and depression. Sexual concerns are common among patients; however, there is evidence to suggest that these concerns are not appropriately investigated by clinicians. Aim To examine the impact of physician gender on sexual history taking. Methods One hundred and thirty-one study questionnaires were sent to OB/Gyns, family practitioners, internists, pediatricians, and surgeons. Physicians were asked to rank their discomfort during interviews with patients of different ages, races, marital status, sexual preference, religious beliefs, and academic achievement, and they were asked to rank their perception of patient discomfort. Main Outcome Measures A cross-sectional descriptive analysis was generated, Fisher's exact test was performed utilizing SPSS software, and confidence intervals were developed utilizing SAS software. Results Of the 78 questionnaires (59%) returned, 69 (88%) reported taking sexual histories. Characteristics identified by physicians as causing discomfort included patient's age younger than 18 and greater than 65, patient's academic achievement below college level, and patient's divorced or single marital status. Moreover, there was a statistically significant difference (P < 0.05) between male and female physicians reporting their discomfort when interviewing males (19% and 50%, respectively) and females (35% and 12%, respectively). Conclusion Although a high percentage of practitioners report taking a sexual history, physicians reported and perceived greatest discomfort when interviewing opposite gender patients as well as patients of very young and old ages. It is clear that not only is there a need for physician education on the topic of sexual history taking, but also consideration of the impact of physician and patient gender.
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