Prenatal Infection Research Articles

Neurological evaluation of microcephalic children with Zika syndrome and congenital cytomegalovirus infection.

IntroductionThe association between the virus prenatal infection by Zika virus (ZIKV) and central nervous system disorders has been well established and it has been described as the Congenital Syndrome Associated to the Zika Virus (CSZ). However, the neurological development in those patients is still an object of study. The main differential diagnosis is the Cytomegalovirus (CMV).ObjectiveDescribe the involvement of microcephalic patients affected by the congenital infection by the Zika Virus or CMV.MethodologyData has been collected from microcephalic patients whose birth took place after 2016 and which also had the congenital infection confirmed or presumed. The researched data consists in: congenital infection, head circumference from birth, presence of epilepsy, treatment by mono or polytherapy, electroencephalographic patterns, neurological physical examination and evaluation of gross motor development.Results21 microcephalic children have been included showing the following congenital infectious syndromes: 9 were affected by cytomegalovirus (43%), 6 by the Zika virus (29%) and 6 ones by presumed infection due to the Zika virus (29%). From those ones, 13 (62%) presented epilepsy diagnosis including generalized crises and 9 (69%) were in current use of polytherapy. All of them also showed disorganized and asymmetrical base rhythms. Concerning the epileptiform activity, 5 presented multifocal activity and 3 ones hypsarrhythmia. All of the patients went under neuroimaging: 12 (57%) of them presented calcifications and 5 (24%) hydrocephalus. On the neurological exam, 17% presented a decreased axial tone and an enlarged appendicular. Smaller head circumference children had greater motor impairment and severity in the epilepsy. There was no difference in the frequency of epilepsy between children with CSZ and CMV.ConclusionEpilepsy is confirmed as one of the most important complications of congenital infections by CSZ and CMV.

Prenatal and Early Childhood Infections and Subsequent Risk of Obsessive-Compulsive Disorder and Tic Disorders: A Nationwide, Sibling-Controlled Study

BackgroundPostinfectious autoimmune processes are hypothesized to be causally related to both obsessive-compulsive disorder (OCD) and tic disorders, but current evidence is conflicting. This study examined whether prenatal maternal (and paternal, as an internal control) infections and early childhood infections in the offspring (i.e., during the first 3 years of life) were associated with a subsequent risk of OCD and Tourette syndrome or chronic tic disorder (TS/CTD). MethodsIndividuals exposed to any prenatal maternal infection (n = 16,743) and early childhood infection (n = 264,346) were identified from a population-based birth cohort consisting of 2,949,080 singletons born in Sweden between 1973 and 2003 and were followed through 2013. Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Sibling analyses were performed to control for familial confounding. ResultsAt the population level, and after adjusting for parental psychiatric history and autoimmune diseases, a significantly increased risk of OCD and TS/CTD was found in individuals exposed to prenatal maternal (but not paternal) infections (OCD: HR, 1.33; 95% CI, 1.12–1.57; TS/CTD: HR, 1.60; 95% CI, 1.23–2.09) and early childhood infections (OCD: HR, 1.19; 95% CI, 1.14–1.25; TS/CTD: HR, 1.34; 95% CI, 1.24–1.44). However, these associations were no longer significant in the sibling analyses. ConclusionsThe results do not support the hypothesis that prenatal maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and TS/CTD.

The association between amniotic fluid-derived inflammatory mediators and the risk of retinopathy of prematurity.

Prenatal and perinatal infections and inflammation appear to associated with the development of retinopathy of prematurity (ROP). In this study, we evaluated whether inflammatory mediators in amniotic fluid (AF) retrieved during cesarean delivery influence the development of ROP in very low birth weight (VLBW) infants.This retrospective study included 16 and 32 VLBW infants who did and did not develop any stage of ROP, respectively. Each infant with ROP was matched with 2 infants without ROP based on days of ventilation care, gestational age, and birth weight. AF was obtained during cesarean delivery, and the levels of intra-amniotic inflammatory mediators such as interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and tumor necrosis factor (TNF)-α were measured using a Human Magnetic Luminex assay (R&D Systems, Minneapolis, MN). The differences in the levels of inflammatory mediators according to the presence or absence of ROP were compared.In patients who developed ROP, the level of MMP-2 in the AF was significantly increased (P = .011), whereas the levels of IL-10 and TNF-α were significantly decreased (P = .028 and .046, respectively) compared with those in infants who did not develop ROP. The levels of the other mediators were not significantly different between the 2 groups. Multivariate regression analysis showed that MMP-2 was a risk factor for the development of ROP (odds ratio, 2.445; 95% confidence interval, 1.170-5.106; P = .017).The concentration of MMP-2 in AF is an independent factor in the development of ROP. Further studies are needed to determine whether the levels of inflammatory mediators in AF affect the ROP severity.

CHARACTERISTICS AND FACTORS ASSOCIATED WITH HEARING LOSS (DEAFNESS) IN CHILDREN ATTENDING THE MEDICAL CITY HOSPITAL, BAGHDAD, IRAQ

Background: Hearing loss (HL) is one of the commonest and neglected childhood disabilities. According to the World Health Organization (WHO), most of childhood hearing impairment is preventable. Studies showed that 31% of hearing impairment cases are caused by prenatal and postnatal infections, 17% are birth-related causes, 4% are ototoxic medications and about 8% related to other causes such as maternal substance abuse. Objective: To review factors associated with HL in a sample of children attending the Medical City Hospital in the Pediatrics Outpatient Clinic and Auditory Clinic; including congenital, early, or late onset and to investigate risk factors associated with HL. Methods: A cross sectional study, included children <15 years with hearing loss attending the Medical City Hospital in the Pediatrics Outpatient Clinic and Auditory Clinic during the period from the 1st of July 2021 till the 30th of October 2021. Results: One hundred and one children with HL; 65.3% of them were males, 71.3% were preschoolers, 60.4% of them had family history of deafness, Severe deafness was found among 45.5% of children. Management was by Cochlear implantation for 60.4% of them and hearing aid for the rest. Causes of deafness were unknown in 39.6% of children, congenital among in 37.6%, acquired in 15.8% and mixed causes in 6.9%. Conclusion: Hearing impairment is severe deafness in most of the children included in this study. Family history, congenital infections and otitis media were the major causes of hearing impairment. Finally, cochlear implant was the management of choice in the majority of these children. Keywords: Hearing loss, cochlear implant, otitis media Citation: Qasim MF, AbdulKareem MN, Issa MA. characteristics and factors associated with hearing loss (deafness) in children attending the Medical City Hospital, Baghdad, Iraq. Iraqi JMS. 2022; 20(1): 68-76. doi: 10.22578/IJMS.20.1.9

Prenatal Exposure to SARS-Cov-2 and Schizophrenia Development: What to Expect?

IntroductionSchizophrenia is a complex and multifactorial psychiatric condition characterized by thought, speech, perception and behaviour disorders, and social and occupational impairment. It has been related that viral prenatal infection may contribute to schizophrenia development. As such, there are some hypotheses regarding SARS-Cov-2 prenatal infection and its potential relation with “future” offspring schizophrenia.ObjectivesLiterature review of schizophrenia development and relation with viral infections, and data research of COVID-19 neurotropic effects.MethodsNon-systematic review through literature using databases as Pubmed and UpToDate. Keywords used: schizophrenia, prenatal, viral infection, COVID-19, SARS-Cov-2.ResultsSeveral studies had shown a relationship between prenatal viral infections, such as Influenza, and development of schizophrenia in the offspring. It relates with viral neurotropism mechanisms and inflammatory processes in the fetal neurology system. Regarding SARS-Cov-2, it is early to assume a relation between prenatal COVID-19 and offspring schizophrenia development. However, literature describes psychiatric manifestations post COVID, such as psychotic and manic episodes. As such, a SARS-Cov-2 neurotropic effect is demonstrated.ConclusionsSchizophrenia has a multifactorial etiology. Since prenatal viral infections may interfere and contribute to schizophrenia development, it is logical to assume prenatal SARS-Cov-2 infection may also contribute. It may be relevant to investigate whether these offspring will manifest schizophrenia symptoms.DisclosureNo significant relationships.

Microcephaly prevalence after the 2015 to 2016 Zika outbreak in Tangará da Serra, Brazil: a population-based study

Abstract Objective: Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics. Methods: Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics. Results: Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was ten-fold higher than that in Latin America before 2015. Conclusion: This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future.

Alternative Therapy of Psychosis: Potential Phytochemicals and Drug Targets in the Management of Schizophrenia.

Schizophrenia is a chronic mental and behavioral disorder characterized by clusters of symptoms including hallucinations, delusions, disorganized thoughts and social withdrawal. It is mainly contributed by defects in dopamine, glutamate, cholinergic and serotonergic pathways, genetic and environmental factors, prenatal infections, oxidative stress, immune system activation and inflammation. Management of schizophrenia is usually carried out with typical and atypical antipsychotics, but it yields modest benefits with a diversity of side effects. Therefore, the current study was designed to determine the phytochemicals as new drug candidates for treatment and management of schizophrenia. These phytochemicals alter and affect neurotransmission, cell signaling pathways, endocannabinoid receptors, neuro-inflammation, activation of immune system and status of oxidative stress. Phytochemicals exhibiting anti-schizophrenic activity are mostly flavonoids, polyphenols, alkaloids, terpenoids, terpenes, polypropanoids, lactones and glycosides. However, well-designed clinical trials are consequently required to investigate potential protective effect and therapeutic benefits of these phytochemicals against schizophrenia.

Possible Routes for Zika Virus Vertical Transmission in Human Placenta: A Comprehensive Review.

Zika virus (ZIKV) infections have gained notoriety due to congenital abnormalities. Pregnant women have a greater risk of ZIKV infection and consequent transmission to their progeny due to the immunological changes associated with pregnancy. ZIKV has been detected in amniotic fluid, as well as in fetal and neonatal tissues of infected pregnant women. However, the mechanism by which ZIKV reaches the fetus is not well understood. The four dengue virus serotypes have been the most widely used flaviviruses to elucidate the host-cell entry pathways. Nevertheless, it is of increasing interest to understand the specific interaction between ZIKV and the host cell, especially in the gestation period. Herein, the authors describe the mechanisms of prenatal vertical infection of ZIKV based on results from in vitro, in vivo, and ex vivo studies, including murine models and nonhuman primates. It also includes up-to-date knowledge from ex vivo and natural infections in pregnant women explaining the vertical transmission along four tracks: transplacental, paracellular, transcytosis mediated by extracellular vesicles, and paraplacental route and the antibody-dependent enhancement process. A global understanding of the diverse pathways used by ZIKV to cross the placental barrier and access the fetus, along with a better comprehension of the pathogenesis of ZIKV in pregnant females, may constitute a fundamental role in the design of antiviral drugs to reduce congenital disabilities associated with ZIKV.

Maternal prenatal infection and anxiety predict neurodevelopmental outcomes in middle childhood.

Prenatal maternal infection and anxiety have been linked, in separate lines of study, with child neurodevelopment. We extend and integrate these lines of study in a large prospective longitudinal cohort study of child neurodevelopment. Data are based on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort; prenatal maternal anxiety was assessed from self-report questionnaire; prenatal infection was derived from reports of several conditions in pregnancy (n = 7,042). Child neurodevelopment at approximately 8 years of age was assessed by in-person testing, reports of social and communication problems associated with autism, and psychiatric evaluation. Covariates included psychosocial, demographic, and perinatal/obstetric risks. Prenatal infection was associated with increased likelihood of co-occurring prenatal risk, including anxiety. Regression analyses indicated that both prenatal infection and prenatal anxiety predicted child social and communication problems; the predictions were largely independent of each other. Comparable effects were also found for the prediction of symptoms of attention problems and anxiety symptoms. These results provide the first evidence for the independent effects of prenatal infection and anxiety on a broad set of neurodevelopmental and behavioral and emotional symptoms in children, suggesting the involvement of multiple mechanisms in the prenatal programming of child neurodevelopment. The results further underscore the importance of promoting prenatal physical and mental health for child health outcomes.

S06.5 (Oral Abstract Presentation): Prenatal infection alters nutrient sensing pathways and amino acid transport in the placenta

S06.5 <i>(Oral Abstract Presentation)</i>: Prenatal infection alters nutrient sensing pathways and amino acid transport in the placenta

Term Infant with Bilateral Parenchymal Brain Hemorrhages.

Term Infant with Bilateral Parenchymal Brain Hemorrhages.

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

PurposePrenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour.ProceduresPregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI).Results[18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits.ConclusionsOur results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.

Infection and higher cortisol during pregnancy and risk for depressive symptoms in adolescent offspring

Prenatal infection, particularly at mid-gestation, has been associated with various psychopathological outcomes in offspring; however, findings linking prenatal infection to offspring depression outcomes have been mixed. Previous research indicates that it may be the co-occurrence of prenatal adversities (e.g., infection and stress) that are associated with depression outcomes in offspring. Nevertheless, no study to date has investigated whether higher levels of biomarkers linked to prenatal stress (e.g., cortisol) in the presence of infection may account for these outcomes. Participants were drawn from the Child Health and Development Studies (CHDS), a prospective, longitudinal study of pregnant women and their offspring. The present study included mother-offspring dyads from the Adolescent Study, a subsample of the CHDS cohort, whose offspring were assessed in adolescence and whose mothers also provided sera to be assayed for cortisol (n = 695). Hierarchical multivariable regressions were conducted to examine whether maternal cortisol during the first and second trimesters of pregnancy interacted with maternal infection to predict increased risk for symptoms of depression in adolescent offspring. There was a significant interaction of second trimester infection and higher cortisol on offspring depression scores during adolescence, controlling for maternal education (p = 0.04). Findings suggest that higher maternal cortisol may sensitize mothers and their offspring to the disruptive influences of infection during mid-pregnancy, conferring greater risk of depressive symptomatology in offspring.

Risk of attention-deficit hyperactivity disorder in offspring of mothers with infections during pregnancy.

Maternal infections during pregnancy are common events that have been suggested to be risk factors for Attention-deficit hyperactivity disorder (ADHD) in offspring. Only a few studies have been conducted to date and results are conflicting. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, considering timing of exposure and the role of fever. We used data from the prospective Norwegian Mother, Father and Child Cohort Study (MoBa), including more than 112,000 pregnancies, linked with data from the Medical Birth Registry of Norway and the Norwegian Patient Registry to estimate odds ratios for the likelihood that children develop ADHD after being exposed to maternal infections during gestation. Children exposed to any maternal infection during pregnancy showed increased risk of receiving an ADHD diagnosis (OR=1.15, CI=1.03-1.27). Specifically, increased ADHD risk was observed after exposure to genitourinary infections in second (OR=1.42, CI=1.06-1.90) or third trimester (OR=2.04, CI=1.19-3.49), and to respiratory infections in second trimester (OR=1.31, CI=1.12-1.54), provided these infections were accompanied by episodes of fever. Increased ADHD risk was also observed after exposure to diarrhea without fever in the third trimester (OR=1.25, CI=1.07-1.46). Overall, our results suggest that prenatal exposure to maternal infections, particularly with co-occurring episodes of fever, are risk factors for ADHD. Fever (or severity of the infection) appears to be more important in mid-pregnancy associations. Our results indicate that type of infection and timing of exposure might influence the associations, but small effect sizes require careful interpretations. The association between infection and ADHD should be estimated using discordant siblings or other negative control designs that give better adjustment for unmeasured familial confounding.

Global RNAseq of ocular cells reveals gene dysregulation in both asymptomatic and with Congenital Zika Syndrome infants exposed prenatally to Zika virus

In 2015, Brazil reported an outbreak identified as Zika virus (ZIKV) infection associated with congenital abnormalities. To date, a total of 86 countries and territories have described evidence of Zika infection and recently the appearance of the African ZIKV lineage in Brazil highlights the risk of a new epidemic. The spectrum of ZIKV infection-induced alterations at both cellular and molecular levels is not completely elucidated. Here, we present for the first time the gene expression responses associated with prenatal ZIKV infection from ocular cells. We applied a recently developed non-invasive method (impression cytology) which use eye cells as a model for ZIKV studies. The ocular profiling revealed significant differences between exposed and control groups, as well as a different pattern in ocular transcripts from Congenital Zika Syndrome (CZS) compared to ZIKV-exposed but asymptomatic infants. Our data showed pathways related to mismatch repair, cancer, and PI3K/AKT/mTOR signaling and genes probably causative or protective in the modulation of ZIKV infection. Ocular cells revealed the effects of ZIKV infection on primordial neuronal cell genes, evidenced by changes in genes associated with embryonic cells. The changes in gene expression support an association with the gestational period of the infection and provide evidence for the resulting clinical and ophthalmological pathologies. Additionally, the findings of cell death- and cancer-associated deregulated genes raise concerns about the early onset of other potential pathologies including the need for tumor surveillance. Our results thus provide direct evidence that infants exposed prenatally to the Zika virus, not only with CZS but also without clinical signs (asymptomatic) express cellular and molecular changes with potential clinical implications.

RSV-induced changes in a 3-dimensional organoid model of human fetal lungs.

We have shown that respiratory syncytial virus (RSV) can spread hematogenously from infected airways of a pregnant woman to the developing fetal lungs in utero. This study sought to measure RSV replication, cytopathic effects, and protein expression in human lung organoids (HLOs) reproducing architecture and transcriptional profiles of human fetal lungs during the 1st trimester of gestation. HLOs derived from human pluripotent stem cells were microinjected after 50 or 100 days in culture with medium or recombinant RSV-A2 expressing the red fluorescent protein gene (rrRSV). Infection was monitored by fluorescent microscopy and PCR. Immunohistochemistry and proteomic analysis were performed. RSV infected HLOs in a dose- and time-dependent manner. RSV-infected HLOs increased expression of CC10 (Club cells), but had sparse FOXJ1 (ciliated cells). Disruption of F-actin cytoskeleton was consistent with proteomic data showing a significant increase in Rho GTPases proteins. RSV upregulated the transient receptor potential vanilloid 1 (TRPV1) channel and, while β2 adrenergic receptor (β2AR) expression was decreased overall, its phosphorylated form increased. Our data suggest that prenatal RSV infection produces profound changes in fetal lungs’ architecture and expression profiles and maybe an essential precursor of chronic airway dysfunction. expression profiles, and possibly be an important precursor of chronic airway dysfunction.

Aberrant newborn T cell and microbiota developmental trajectories predict respiratory compromise during infancy

SummaryNeonatal immune-microbiota co-development is poorly understood, yet age-appropriate recognition of – and response to – pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 preterm and 119 full-term infants from birth through one year of age, we found that postmenstrual age or weeks from conception is a central factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained; however, by either age metric and are instead shaped by discrete perinatal and postnatal events. Most strikingly, we establish that prenatal antibiotics or infection disrupt the normal T cell population developmental trajectory, influencing subsequent respiratory microbial colonization and predicting respiratory morbidity. In this way, early exposures predict the postnatal immune-microbiota axis trajectory, placing infants at later risk for respiratory morbidity in early childhood.

Congenital syphilis re-emergence in Winnipeg, Manitoba.

Infectious syphilis rates have been increasing in Winnipeg, Manitoba among individuals during their childbearing years. Untreated or inadequately treated prenatal infection often results in congenital syphilis, with devastating consequences to fetal health and survival. The objective of this study was to review public health surveillance data regarding congenital syphilis incidence and birthing parent risk factors in Winnipeg from 2018 to 2020. Data extracted from a population-based surveillance database maintained by the Winnipeg Regional Health Authority Public Health investigations for all 2018-2020 probable or confirmed cases of early congenital syphilis or syphilitic stillbirth were reviewed. Rates of congenital syphilis were calculated per 1,000 live births. Descriptive analyses were performed to describe birthing parent age, neighbourhood of residence, intravenous substance use, Child and Family Services involvement, access to prenatal care and obtainment of adequate prenatal treatment. There were eight cases of confirmed/probable congenital syphilis in 2018, 22 cases in 2019 and 30 cases in 2020. Average birthing parent age was 26.5-27.0 years. The majority (66.7%) of birthing parents lived in inner city neighbourhoods with known infectious syphilis outbreaks. Over 50% of birthing parents did not receive any prenatal care, or the care received consisted of inadequate treatment or follow-up. Reinfection among birthing parents who did receive prenatal care was suspected in an additional 23.3% of cases. Congenital syphilis rates in Winnipeg have increased dramatically. Public health and healthcare provider efforts to address the needs of the community are vital for promoting access to safe and effective prenatal care.

Prenatal Influenza Vaccination or Influenza Infection and Autism Spectrum Disorder in Offspring.

As prenatal vaccinations continue to be given more frequently, it is important to assess long-term safety events. We investigated the association between prenatal influenza vaccination or infection and autism spectrum disorder (ASD) in offspring. A retrospective cohort study of mother-child pairs with deliveries between 1 January 2011 and 31 December 2014 at Kaiser Permanente Southern California was performed. Children aged >1 year were followed through 31 December 2018. Maternal influenza vaccination or infection during pregnancy was obtained from electronic health records. ASD was defined by International Classification of Diseases, Ninth or Tenth Revisions, Clinical Modification, codes after age 1 year. Cox proportional hazard models estimated the crude and inverse probability of treatment weighted (IPTW) hazard ratios (HR) for the association between maternal influenza vaccination or infection and ASD. There were 84739 mother-child pairs included in the final analytic sample. Of the 46257 women vaccinated, 32.4% were vaccinated during the first trimester, 41.8% during the second trimester, and 25.8% during the third trimester. ASD was diagnosed in 1930 (2.3%) children. The IPTW analyses showed no association between prenatal influenza vaccination or infection and ASD in offspring (HR, 1.04; 95% confidence interval [CI], .95-1.13; HR, 1.12; 95% CI, .66-1.89, respectively). Prenatal influenza vaccination or infection was not associated with ASD risk in offspring. The findings support recommendations to vaccinate pregnant women to protect themselves and their infants, both of whom are vulnerable to severe morbidity following infection.

Transgenerational Sex-dependent Disruption of Dopamine Function Induced by Maternal Immune Activation.

Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by in vivo electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors’ polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.