Prenatal Infection Research Articles

A proof-of-concept study of maternal immune activation mediated induction of Toll-like receptor (TLR) and inflammasome pathways leading to neuroprogressive changes and schizophrenia-like behaviours in offspring

Infection, particularly prenatal infection, leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes that drive prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviours through activation of TLR and inflammasome pathways in the brain of offspring.Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-6, TNF-α and IL-17A assessed after 24 hours were observed in both the poly (I:C) and LPS-treated rats, while IL-1β was only elevated in LPS-treated rats, indicating MIA. The offspring of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviours, deficits in social behaviours and prepulse inhibition. The hippocampus of offspring rats showed increased expression of Tlr3, Tlr4, Nlrp3, Il1b, and Il18 of poly (I:C) and Tlr4, Nlrp3, Cas1, Il1b, and Il18 of LPS-treated dams. Furthermore, Tlr and inflammasome genes were associated with social deficits and impaired prepulse inhibition in offspring rats. The results suggest that MIA due to prenatal infection can trigger TLR and inflammasome pathways and enhances the risk of schizophrenia-like behaviours in the later stages of life of the offspring.

Psychometric properties of the Italian version of the Pandemic-Related Pregnancy Stress Scale (PREPS) and its correlation with anxiety and depression

Background: In the beginning of 2020, Italy was the first European country to face the COVID-19 outbreak. Restrictions imposed during the pandemic, social isolation, and the cancellation of medical appointments likely resulted in stress that may have affected pregnant women adversely.Aims: To determine the psychometric validity of the Italian version of the Pandemic-Related Pregnancy Stress Scale (PREPS) in assessing COVID-19-related stress in pregnant women and to examine correlations between PREPS scales and symptoms of anxiety and depression.Methods: 232 pregnant women attending the Obstetric-Gynecologic Clinic of an Academic Hospital were assessed with the PREPS, the Revised Prenatal Distress Questionnaire (NuPDQ), the General Anxiety Disorder-7 (GAD-7), and the Patient Health Questionnaire-2 (PHQ-2). We analyzed the internal consistency and factor structure of the PREPS. Convergent validity was examined by comparison with the NuPDQ. PHQ-2 and GAD-7 were used to measure the association with depression and anxiety.Results: Acceptable-to-good internal consistency was found for the three PREPS scales: Preparedness Stress (PS, α=0.760), Prenatal Infection Stress (PIS, α=0.857), and Positive Appraisal (PA, α=0.747). Correlations of the NuPDQ with both PREPS stress scale scores (PS and PIS) were statistically significant, but on multiple regression analysis only the PS scale was correlated with the NuPDQ. Prenatal infection stress predicted GAD-7 score, while Preparedness stress predicted PHQ-2 score.Limitations: The main limitations were the small sample size and the cross-sectional design of the study.Conclusion: The Italian PREPS exhibited good psychometric properties and associations with clinical symptoms of anxiety and depression.

Research protocol for homeopathic treatment of congenital zika virus infection

Background The Zika virus (ZIKV) is a flavivirus and the human disease caused by this virus has been described in the Americas in 2015. ZIKV has been identified as an etiological agent of acute exanthematous disease in Brazil. In the same year, an epidemic of microcephaly with images suggestive of congenital infection raised the suspicion of a relationship between these alterations and ZIKV infection. Epidemiological and histopathological studies point to a strong relationship between prenatal Zika virus infection and microcephaly. Newborns with microcephaly, may also present auditory and visual changes, seizures and severe neurodevelopmental impairment. In 2016, the World Health Organization (WHO) declared Zika virus (ZIKV) infection a public health emergency of international concern. Aims Clinical observation in the ambulatory school of ABRAH (Brazilian Association of Recycling and Homeopathy Assistance) of patients with encephalopathy of various origins, using the medicine Helleborus niger as equalizer of the NS (Nervous System), as described in the Complex Systems of Carillo, shows improvement in motor, cognitive and seizure disorders. Based on this observation, we propose to use this method in patients with ZIKV congenital infection. Methodology To evaluate 15 patients in follow-up at the AFR (Fluminense Rehabilitation Association), through homeopathic anamnesis, clinical, diathesic, biotypological and temperamental classification. The Gross Motor Function Classification System (GMFCS) will be used. All patients will receive Helleborus niger 6 Ch daily for 6 months. Results and discussion This study was forwarded to the research ethics committee and will begin in July 2019. 
 Will be evaluated the use of Helleborus niger in patients with congenital infection by ZIKV, as equalizer of NS. The expected result is overall neurological improvement. Conclusion Helleborus niger, probably stimulating self-regulation through uninjured neurological pathways, will promote autopoiesis and construction of new programs of action, and will enable the improvement of patients with congenital ZIKV infection.

Auditory and Language Development Assessment of Newborns Aged One to Four Years Exposed to Gestational Zika Virus Infection: A Case Series

The known neurotropism of the Zika virus (ZikV) suggests that auditory organs and their neural pathways may be affected by prenatal Zika infections. Among the possible manifestations are audiological and language disorders, but so far, the data in the literature are inconclusive. Objective: To describe early and late hearing disorders in children with Congenital Zika Virus Infection (CZVI) and evaluate the language development of this population between 14 and 47 months of age and its possible correlation with the alterations found in auditory exams. Methods: Longitudinal, prospective, observational study of newborns born in Juiz de Fora and its macroregion with confirmed diagnosis of ZikV infection during pregnancy. Participants were examined from one to four years of age for hearing using the transient otoacoustic emissions (TOAE) test, immittance testing and brainstem auditory evoked potential (BAEP), and language using the Bayley Scales of Infant Development—Third Edition (Bayley III). Results: 15 participants were included; eight (53.33%) presented alterations in at least one of the hearing tests, one had an early loss (6%) of sensorineural origin, and seven (46.67%) had a poor language performance. In the three (20%) participants whose audiological exams were altered, there was language impairment, and two (13.33%) participants had extensive malformations in the central nervous system (CNS), presented language delay, and hearing exams were within normality. Conclusion: Infants and preschoolers with CZVI may present early neurosensory loss and late hearing loss with fluctuating character. Even if there were no significant association between the audiological exams results and the Bayley III performance, in the present sample, language development was below expectations for the age in the participants who had alterations in the three audiological exams, when there is early hearing loss or extensive lesions to the CNS. The results reinforce the importance of audiological examinations, especially the BAEP morphological and auditory threshold, in monitoring cases of CZVI until at least three years of age.

An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach.

Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.

COVID-19 Infection During Pregnancy and Associated Perinatal Health Outcomes: A National Cohort Study of US Pregnancies

Background: Emerging evidence suggests that COVID-19 infection is more severe in pregnant individuals and may be associated with increased risk of adverse perinatal health outcomes. However, few large-scale, community-based comparative epidemiological studies have evaluated pregnancy outcomes following COVID-19 infection.Methods: We conducted a national cohort study using de-identified administrative claims and electronic health record data from the OptumLabs® Data Warehouse. Every pregnancy with a last menstrual period before 30 April 2020 and date of pregnancy end after 11 March 2020 was included. We identified maternal infections using ICD-10-CM diagnostic code of U07.1 or a positive laboratory testing record for SARS-CoV-2. We compared the risk of adverse pregnancy outcomes using Cox proportional hazard models treating COVID-19 infection as a time-varying exposure, which were adjusted for baseline covariates.Findings: Of the 78,283 pregnancies identified, 2,655 (3·4%) had a documented COVID-19 infection. Infection was more prevalent among Black and Hispanic pregnant individuals and those with pre-existing medical conditions; 3·4% of COVID-19 cases required admission to intensive care, invasive mechanical ventilation or ECMO treatment. COVID-19 during pregnancy was associated with higher risk of medical termination (adjusted hazard ratio [aHR] 2·60; 95% CI 1·17, 5·78), cesarean section (aHR 1·99; 95% CI 1·71, 2·31), clinician-initiated preterm birth (2·88; 95% CI 1·93, 4·30), spontaneous preterm birth (aHR 1·79; 95% CI 1·37, 2·34), and fetal growth restriction (aHR 2·04; 95% CI 1·72, 2·43). Similar associations were observed by trimester of COVID-19 infection.Interpretation: Data from this US pregnancy cohort show increased risk of adverse pregnancy outcomes associated with prenatal COVID-19 infection during any trimester of pregnancy. Prevention of COVID-19 through vaccination, social distancing and other measures could prevent COVID-19-associated adverse pregnancy outcomes. Funding Information: Access to study data was financially supported by OptumLabs® and University of California Los Angeles. The WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health.Declaration of Interests: We declare no competing interests.Ethics Approval Statement: Because this study involved analysis of pre-existing, de-identified data, it was considered exempt from Institutional Review Board approval.

Causes of Phenotypic Variability and Disabilities after Prenatal Viral Infections.

Prenatal viral infection can lead to a spectrum of neurodevelopmental disabilities or fetal demise. These can include microencephaly, global developmental delay, intellectual disability, refractory epilepsy, deafness, retinal defects, and cortical-visual impairment. Each of these clinical conditions can occur on a semi-quantitative to continuous spectrum, from mild to severe disease, and often as a collective of phenotypes. Such serious outcomes result from viruses’ overlapping neuropathology and hosts’ common neuronal and gene regulatory response to infections. The etiology of variability in clinical outcomes is not yet clear, but it may be related to viral, host, vector, and/or environmental risk and protective factors that likely interact in multiple ways. In this perspective of the literature, we work toward understanding the causes of phenotypic variability after prenatal viral infections by highlighting key aspects of the viral lifecycle that can affect human disease, with special attention to the 2015 Zika pandemic. Therefore, this work offers important insights into how viral infections and environmental teratogens affect the prenatal brain, toward our ultimate goal of preventing neurodevelopmental disabilities.

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID-19-babies.

Intragravidic and perinatal infections, acting through either direct viral effect or immune‐mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up‐to‐date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID‐19 longitudinal studies.

Global Distribution and Genetic Heterogeneity of Border Disease Virus.

Border disease virus (BDV) belongs to the genus Pestivirus of the family Flaviviridae. Interspecies transmission of BDV between sheep, cattle, and pigs occurs regularly, sometimes making diagnosis a challenge. BDV can yield substantial economic losses, including prenatal and postnatal infections in lambs, which are the primary source of infection and maintenance of the virus in the population. Since BDV is antigenically and genetically related to bovine viral diarrhea virus (BVDV), it might pose a significant risk to cattle, influencing BVDV eradication campaigns. Similarly, the presence of BDV in swine herds due to pestivirus spillover between small ruminants and pigs might cause uncertainty in classical swine fever virus (CSFV) diagnostics. Therefore, knowledge of BDV epidemiology in different geographical regions will help prevent its spread and optimize control measures. Previous epidemiological studies have shown that various BDV genotypes are predominant in different countries. This review provides an overview of the spread of BDV world-wide in different host species.

Prenatal Maternal Infections and Children’s Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD

Objective: No clear answer has yet been attained as to the influence of prenatal exposure to infection on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), either alone or as co-occurring issues. The current study examined links between hospital-recorded and maternal-reported prenatal infections and ASD, ADHD, and co-occurring ASD and ADHD. Methods: Participants were n = 15,462 children and mother pairs from the Millennium Cohort Study (MCS), a population-representative UK sample. Results: Findings show associations between maternal-reported infections and ASD, and some evidence of links with ADHD and co-occurring ASD and ADHD. Hospital-recorded infections were not found to be associated with ASD, ADHD, or their co-occurrence. Agreement between hospital-recorded and maternal-reported infections was low, which may explain the discrepant findings. Conclusion: Prenatal maternal infections may be associated with increased odds of ASD and ADHD. Findings point to the importance of drawing on multiple sources of information when ascertaining prenatal infection status.

Prenatal infection and schizophrenia: A decade of further progress

Epidemiologic studies have provided evidence that prenatal exposure to maternal infection is associated with an increased risk of developing schizophrenia in the offspring. Research over the past decade has added further to our understanding of the role of prenatal infection in schizophrenia risk. These investigations include several well-powered designs, and like some earlier studies, measured maternal antibodies to specific infectious agents in stored serum samples and large registers to identify clinically diagnosed infections during pregnancy. Convergent findings from antibody studies suggest that prenatal maternal infection with Toxoplasma gondii is associated with increased schizophrenia risk in the offspring, while associations with HSV-2 infection are likely attributable to confounding. Maternal influenza infection remains a viable candidate for schizophrenia, based on an early serological study, though there has been only one attempt to replicate this finding, with a differing methodology. A prior association between maternal serologically confirmed cytomegalovirus infections require further study. Clinically diagnosed maternal infection, particularly bacterial infection, also appears to be associated with increased risk of offspring schizophrenia, and heterogeneity in these findings is likely due to methodological differences between studies. Further clarification may be provided by future studies that address the timing, type, and clinical features of infections. Important insight may be gained by examining the long-term offspring outcomes in emerging epidemics such as Zika virus and COVID-19, and by investigating the interaction between exposure to prenatal infection and other risk or protective factors.

Nonsyndromic Oral clefts and associated risk factors in Gansu Province, Northwest of China

PurposeThis study aimed to investigate the incidence of demographic and parental risk factors among patients with nonsyndromic oral cleft (NSOC) in Gansu Province, Northwest China. Patients and MethodsA multicenter study was conducted on patients with NSOC who received care in our centers between January 2017 and January 2019. Demographic data, pregnancy associated risk factors, hereditary history and consanguineous marriage were collected. Chi-square test was tabulated to identify the statistical significance of the data. P-value < 0.05 was regarded as statistically significant. ResultsA total of 600 patients with NSOC were enrolled in the present study. Among the cases, 26.8 % were CL, 50.2 % were CLP, and 23 % were isolated CP. The ratio of boys to girls was higher in CL (1.5:1) and CLP (1.8:1), while CP recorded a lower ratio (0.5:1). Most of cases had type O blood group (40 %) and were the first births in their families (53.5 %). Higher rates of cases were born in winter (28.3 %) and spring (28.2 %), with a peak incidence in April (11.5 %). Most of presented cases were born by late parental middles age (25−29 years). Maternal passive smoking, paternal smoking and drinking, infectious diseases, abortion history, and drug use recorded the highest rates (53.8 %, 53.3 %, 50 %, 30.5 %, 23.3 %, and 18.7 %, respectively) among all parental risk factors. Among all demographic and parental risk factors, birth seasonality, early paternal middle age, prenatal infection, and fever were found to have a significant tendency for a certain cleft type or sex of patient. ConclusionNSOC is a complex disease, could be the result of a combination of genetic and environmental factors. Familial history, consanguinity, seasonal changes, infections, fever, drug use, parental ages, and passive smoking are among risk factors that may be associated with NSOC. Our findings could provide references for proper resource use, NSOC prevention programs, and will contribute in minimizing the incidence of NSOC in the area of study.

Incidence of schizophrenia and influence of prenatal and infant exposure to viral infectious diseases

There is conflicting evidence in recent literature about whether the incidence of schizophrenia is increasing or decreasing. A role for prenatal and early childhood viral infections in the aetiology of schizophrenia has also been debated. We examined the incidence of schizophrenia and the catatonic subtype of schizophrenia over a 30-year period in Finland. We also investigated whether the incidence rate of the catatonic subtype of schizophrenia was linked to changes in exposure to viral infection (polio and measles) during the prenatal or infant period. Persons with schizophrenia were identified from the Hospital Discharge Register. Cumulative incidence of schizophrenia from 1956 to 1989 in 4 age groups was calculated with follow-up from 1972 to 2014. Annual rates of polio and measles were derived from nationwide registers. The association between log-transformed polio and measles incidence and incidence of schizophrenia, and specifically catatonic schizophrenia, were analysed using linear models. Cumulative incidence of schizophrenia among individuals born 1956-1989 decreased by 23% (from 13 to 10 cases per 1000 live births). The decline was the most prominent in those with onset of schizophrenia diagnosed 16-25years of age (-41%). The incidence of catatonic schizophrenia declined by 90% over three decades, and there was a significant association between annual polio incidence during the birth year and incidence of catatonic schizophrenia. The results indicate that the incidence of schizophrenia in Finland has declined for individuals born between 1956 and 1989, and that the decline of catatonic schizophrenia may be partially attributable to eradication of polio.

Possible risk of fetal development of autism in pregnant women infected by SARS-CoV-2

Introduction. In March 2020, the World Health Organization (WHO) announced the emergence of a global pandemic, COVID-19. A disease triggered by the new coronavirus infection (SARS-CoV-2). More recent findings indicate that the gestational period makes the mother and her offspring more susceptible to the new coronavirus and the rapid progression to the critical stage of the disease. The maternal organism presents a certain degree of immunological and cardiorespiratory deficiency due to physiological adaptations to the gestational period and, consequently, if affected by prenatal infections caused by viruses, they lead to an exacerbated Maternal Immune Activation (MIA), thus contributing to alterations in maternal-fetal neurogenesis, fetal myelinization, and is directly involved in the pathogenesis of neurodevelopmental disorders in the offspring, especially autism. Objective. This study hypothesizes that maternal COVID-19 infections during pregnancy are a potential risk for the offspring to develop Autism Spectrum Disorder. Conclusion. The exposure to viral infectious agents during the gestational period leads to exacerbated maternal immune activation. It contributes to alterations in maternal-fetal neurogenesis and is directly involved in the pathogenesis of neurodevelopmental disorders, being correlated to the predisposition to affective and psychiatric disorders in the offspring. Therefore, greater attention should be given to the offspring of pregnant women infected by COVID-19, since prenatal infectious processes have a strong correlation with the prevalence of Autistic Spectrum Disorder in the offspring.

Prenatal maternal infection and risk for autism in offspring: A meta-analysis.

While prenatal maternal infection has received attention as a preventable and treatable risk factor for autism, findings have been inconsistent. This paper presents the results of a meta-analysis to determine whether the weight of the evidence supports such an association. Studies with a categorical diagnosis of autism as the outcome and an assessment of its association with prenatal maternal infection or fever (or the data necessary to compute this association) were included. A total of 36 studies met these criteria. Two independent reviewers extracted data on study design, methods of assessment, type of infectious agent, site of infection, trimester of exposure, definition of autism, and effect size. Analyses demonstrated a statistically significant association of maternal infection/fever with autism in offspring (OR=1.32; 95% CI=1.20-1.46). Adjustment for evident publication bias slightly weakened this association. There was little variation in effect sizes across agent or site of infection. Small differences across trimester of exposure were not statistically significant. There was some evidence that recall bias associated with status on the outcome variable leads to differential misclassification of exposure status. Nonetheless, the overall association is only modestly reduced when studies potentially contaminated by such bias are removed. Although causality has not been firmly established, these findings suggest maternal infection during pregnancy confers an increase in risk for autism in offspring. Given the prevalence of this risk factor, it is possible that the incidence of autism would be reduced by 12%-17% if maternal infections could be prevented or safely treated in a timely manner. LAY SUMMARY: This study is a meta-analysis of the association of maternal infection during pregnancy and subsequent autism in offspring. In combining the results from 36 studies of this association we find that a significant relationship is present. The association does not vary much across the types of infections or when they occur during pregnancy. We conclude that the incidence of autism could be substantially reduced if maternal infections could be prevented or safely treated in a timely manner.

Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35–49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2–ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats.

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

Nodular Lesion in a Newborn with Spontaneous Regression.

1. Xavier Sanchez-Flores, MD* 2. Oscar W. Nevares-Pomales, MD* 3. Rafael F. Martin-Garcia, MD* 1. *Department of Dermatology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico A 4-week-old girl presents to the dermatology clinic with a nodular lesion over her right ala nasi that has been present since birth. She was born via spontaneous vaginal delivery at 39 weeks’ gestation as the first child to a healthy 29-year-old woman after an uncomplicated pregnancy and delivery. The mother reports no history of prenatal infection or complication. Neonatal growth parameters such as weight, length, and head circumference are within the normal ranges. Apgar scores were normal. Results of prenatal screening laboratory tests for group B streptococcus, hepatitis B, rubella antibodies, urinalysis, syphilis, complete blood cell count, and human immunodeficiency virus were reassuring. The family and social histories are noncontributory. The patient was born with a small, nonblanchable erythematous papule that rapidly grew to a yellowish-brown nodule with central crust (Fig 1). The lesion did not collapse on compression. There is no liver or spleen enlargement, fever, icterus, involvement of mucous membranes or superficial palpable lymphadenopathy. No other significant skin manifestations are observed. Results of diagnostic tests, including complete blood cell count, complete metabolic panel, coagulation profile, chest radiograph, whole-body scintigraphy, and newborn screening, are normal. The hematology-oncology service is consulted, but a bone marrow biopsy reveals no abnormalities or concerning findings. S-100 and CD1a stains are negative in the bone marrow sample. A skin biopsy reveals the diagnosis. Figure 1. Erythematous, ulcerated nodule with mild crusting. The skin biopsy demonstrates an ulcerated epidermis with a diffuse and lichenoid mixed dermal infiltrate mostly composed of large cells with kidney-shaped reniform nuclei along with scattered lymphocytes and few eosinophils. Immunohistochemical staining with CD1a and S-100 shows strong reactivity in …

Pregnancy complications among refugee women: A systematic review.

Pregnancy is a time of increased vulnerability for women. Women of refugee background may be further challenged in pregnancy due to a complex series of physical, psychological and social factors. Previous studies show ambiguous results, with some showing increased the risk of prenatal complications in refugees compared with their native counterparts, whereas other studies report the opposite. With the current steep rise in the number of refugees and displaced persons worldwide, research is important to understand whether pregnancy disparities between this population and their native counterparts exist, and the causes. This systematic literature review aims to find out whether refugee women have a higher prevalence of adverse pregnancy outcomes and prenatal infections compared with native women. We conducted a literature search in the databases PubMed and Embase, supplemented with screening of reference lists and citations for relevant literature. We included studies published in English reporting risk of preeclampsia, spontaneous abortion and stillbirths, preterm birth, preterm prelabor rupture of membranes (PPROM) and adverse prenatal infectious diseases in women of refugee status. PROSPERO registration CRD42020205628. We identified 19 articles eligible for inclusion: 12 were cross-sectional, six were cohort studies and one was a case-control study. The most frequently reported outcome in the literature was preterm birth (reported in 16 of the studies) and preeclampsia (reported in 11 of the studies). Refugees had increased risk of stillbirth (reported relative risk ranging from 1.20 to 2.24) and spontaneous abortion (reported relative risk ranging from 1.56 to 1.58), when compared with native women and a decreased risk of preeclampsia (reported relative risk ranging from 0.65 to 0.81). The small number of articles eligible for inclusion in the review highlights the lack of research and knowledge on refugee health during pregnancy. Further research is required to understand and reduce disparities in pregnancy outcomes between refugee and non-refugee women.

Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation.

BackgroundCoxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation.Methods and ResultsWe infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls.ConclusionsWe conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.