Prenatal Infection Research Articles

Zika virus infection causes widespread damage to the inner ear

Zika virus (ZIKV) has been recently recognized as a causative agent of newborn microcephaly, as well as other neurological consequences. A less well recognized comorbidity of prenatal ZIKV infection is hearing loss, but cases of hearing impairment following adult ZIKV infection have also been recognized. Diminished hearing following prenatal ZIKV infection in a mouse model has been reported, but no cellular consequences were observed. We examined the effects of ZIKV infection on inner ear cellular integrity and expression levels of various proteins important for cochlear function in type I interferon receptor null (Ifnar1−/−) mice following infection at 5–6 weeks of age. We show that ZIKV antigens are present in cells within the cochlear epithelium, lateral wall, spiral limbus and spiral ganglion. Here we show that ZIKV infection alters cochlear expression of genes that signal cell damage (S100B), transport fluids (AQP1), are gaseous transmitters (eNOs) and modulate immune response (F4/80). Morphological analyses shows that not only are cochlear structures compromised by ZIKV infection, but damage also occurs in vestibular end organs. ZIKV produces a graded distribution of cellular damage in the cochlea, with greatest damage in the apex similar to that reported for cytomegalovirus (CMV) infection. The graded distribution of damage may indicate a differential susceptibility to ZIKV along the cochlear tonotopic axis. Collectively, these data are the first to show the molecular and morphological damage to the inner ear induced by ZIKV infection in adults and suggests multiple mechanisms contributing to the hearing loss reported in the human population.

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus.

Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.

Low Prenatal Choline, Maternal Infection Linked to Attention Problems

Low Prenatal Choline, Maternal Infection Linked to Attention Problems

Maternal choline and respiratory coronavirus effects on fetal brain development

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6–16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants’ level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 μM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.

O10.1. MATERNAL PRENATAL C-REACTIVE PROTEIN, NEURODEVELOPMENT AND OTHER RISK FACTORS FOR PSYCHOSIS IN ADOLESCENT OFFSPRING IN THE NORTHERN FINLAND BIRTH COHORT 1986

BackgroundPrenatal infection is associated with brain structural and functional abnormalities, and may increase risk for psychosis through a direct effect on neurodevelopment. Proinflammatory immune response may be a common mechanism through which various infections exert their harmful effect, but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. We examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring including markers of neurodevelopment and cannabis use.MethodsThis study used a longitudinal birth cohort, the Northern Finland Birth Cohort 1986 (NFBC 1986), followed up to age 16 years (n=6,985/9,432, 76% follow-up). CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 and 16y; psychotic experiences and cannabis use was measured at age 16. Controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy using regression analysis, we tested associations of CRP with offspring measures. We also tested for mediation, specifically if adolescent cannabis use mediated the associations between maternal CRP and offspring psychotic experiences and school performance.ResultsBased on data from a minimum of 4,153 participants, after controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy, maternal CRP was associated with adolescent neurodevelopmental markers, including psychotic experiences (odds ratio=1.13, 95% CI=1.00–1.29) and academic performance at age 16 years (beta=0.063, SE=0.013, 95% CI=0.037–0.089). Maternal CRP was also associated with adolescent cannabis use (odds ratio=1.27, 95% CI=1.11–1.46). Cannabis use appeared to mediate a small amount of the associations between maternal CRP and both psychotic experiences and academic performance.DiscussionThese results support a neurodevelopmental role for maternal prenatal infection and offspring psychosis but also suggest an indirect effect through increasing risk of exposure to cannabis. Maternal infection and immune activation may impact on brain circuitry involved in impulsivity, increasing behaviours such as cannabis use that are separately associated with psychosis. The results of this study give clues regarding the mechanism of the maternal inflammation – psychosis association and add to our understanding of the complex neurodevelopmental processes predating psychosis.

From Prenatal Maternal Inflammation to Adolescent Depression Through Childhood Psychiatric Symptoms: Timing and Sex Matter

Evidence links prenatal infection and stress with offspring adolescent depression. Our previous study found that markers of prenatal maternal inflammation (MI) were associated with two childhood outcomes, internalizing and externalizing symptoms, associated with increased risk of depression. The present study sought to investigate whether MI was associated with offspring adolescent depression and whether childhood psychiatric symptoms mediated this association. We also examined sex differences and timing of exposure.

Impact of Syrian refugees on congenital TORCH infections screening in Turkey

To demonstrate the effect of the Syrian refugee population on the prevalence of congenital TORCH (Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus [CMV] and Herpes) infections and to evaluate the cost-effectiveness of population-based TORCH screening during pregnancy in Turkey. Pregnant women (n = 9754) were enrolled. Ultrasonographic findings, immunoglobulin (Ig)M and IgG seropositivity, avidity, amniocentesis and DNA-polymerase chain reaction (PCR) results were compared. Costs were calculated based on invoice amounts from the Health Applications Communique pricing system. The prevalence of TORCH seropositivity in Turkey was not significantly different between all regions (P > 0.05). Overall, 1333 (13.67%) pregnant Syrian refugees were included in the study. Acute CMV, rubella and Toxoplasma gondii infections (according to low IgG avidity in IgM positive patients) were detected in 17.82%, 21.53% and 14.07% of women, respectively. Twenty-four women underwent an amniocentesis procedure and nine of them had positive DNA-PCR and reverse transcription-PCR results. All women with positive results opted to terminate the pregnancy. There was no statistical difference among groups according to the rate of low IgG avidity in IgM-positive patients and termination rates for T. gondii, rubella and CMV (P > 0.05). Total cost for screening the entire study population was presented in US dollars (USD). A total of 71 529 and prenatal diagnosis with positive invasive test results were obtained in nine women: toxoplasmosis in four, CMV in three and rubella in two women. Population-based screening for prenatal TORCH infections is not cost-effective in Turkey. Syrian refugees have a limited effect on the increasing prevalence of congenital TORCH infections.

Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder

Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.

The Sero-Prevalence of Cytomegalovirus Infection among Women with Abortion and Intrauterine Death in Erbil City Kurdistan Region , Iraq

Background: Cytomegalovirus (CMV) is a major causative agent of prenatal and perinatal infections and may lead to important complications on pregnancy. Objective: To find out the sero-prevalence of CMV IgM and IgG and its association with the history of abortion and / or intra-uterine death, as well as, to study the association between the mentioned prevalence with some socio-demographic variables. Patients and Methods: A case-control study was performed during the period between October 2018 to April 2019 in Erbil city (Kurdistan region, Iraq) on 75 pregnant women with history of abortion and / or intra-uterine death; and 75 healthy women with normal pregnancy who served as a control group. The women had been referred to the central laboratory department of the Maternity Teaching Hospital for the detection and evaluation of sero-prevalence of CMV specific IgM and IgG markers. The study was approved by the Ethics Committee of Health Sciences College, Hawler Medical University and informed consent was obtained from the patients and controls. Results: The sero-prevalence of CMV-specific IgG was 100% in each of the study groups. The sero- prevalence of CMV-specific IgM was 8% among women with abnormal pregnancy, while, none of the women of the control group had a positive IgM. No significant association was detected between CMV-specific IgM sero-prevalence and any of the studied sociodemographic factors as well as risk factors including abortion, intrauterine death and hypertension (p>0.05). Conclusion: The association was detected between the CMV-specific IgM sero-prevalence and history of abortion and / or intra-uterine death but no significant may be due to small sample size in the present study.

Bone marrow stem cells accelerate lung maturation and prevent the LPS-induced delay of morphological and functional fetal lung development in the presence of ErbB4.

ErbB4 is a regulator in lung development and disease. Prenatal infection is an important risk factor for the delay of morphologic lung development, while promoting the maturation of the surfactant system. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to prevent lung injury. We hypothesized that BMSCs in comparison with hematopoietic control stem cells (HPSCs) minimize the lipopolysaccharide (LPS)-induced lung injury only when functional ErbB4 receptor is present. We injected LPS and/or murine green fluorescent protein-labeled BMSCs or HPSCs into the amniotic cavity of transgenic ErbB4heart mothers at gestational day 17. Fetal lungs were analyzed 24h later. BMSCs minimized significantly LPS-induced delay in morphological lung maturation consisting of a stereologically measured increase in mesenchyme and septal thickness and a decrease of future airspace and septal surface. This effect was more prominent and significant in the ErbB4heart+/- lungs, suggesting that the presence of functioning ErbB4 signaling is required. BMSC also diminished theLPS induced increase in surfactant protein (Sftp)amRNA and decrease inSftpcmRNA is only seen if ErbB4 is present. The reduction of morphological delay of lung development and of levels of immune-modulating Sftp was more pronounced in the presence of the ErbB4 receptor. Thus, ErbB4 may be required for the protective signaling of BMSCs.

Adenovirus and RSV infections during pregnancy and their relationship to orofacial clefts

This article reports the relationship between prenatal respiratory infections such as human respiratory adenovirus (HRAV) and/or human respiratory syncytial virus (HRSV) and orofacial clefts (OFC). Specific antibodies against HRAV and HRSV were investigated serologically (ELISA) in newborns with orofacial cleft and their mothers. The results were compared with those obtained from healthy newborns (controls) and their mothers. Statistical evaluation revealed significant changes in HRAV IgA antibodies between mothers of children with OFC and mothers with healthy newborns. HRSV antibodies of newborns with OFC were changed only marginaly (p = 0.0665) compared to controls. Our results indicate possible involvement of HRSV and HRAV in congenital orofacial defects, however these results have to be confirmed in larger scale study.

Внутриутробные инфекции в структуре ранней неонатальной смертности

Внутриутробные инфекции в структуре ранней неонатальной смертности

Association between prenatal maternal infection and disordered eating behaviours in adolescence: A UK population-based prospective birth cohort study

Association between prenatal maternal infection and disordered eating behaviours in adolescence: A UK population-based prospective birth cohort study

548: Development and assessment of prenatal CMV infection education in a diverse metropolitan area

Congenital CMV infection can result in serious sequelae in the newborn. The goal of this study was to assess pregnant women's baseline knowledge and understanding of CMV infection during pregnancy and develop an educational tool on CMV infection to be utilized during prenatal care. This is a prospective intervention study that assessed pregnant women’s knowledge before and after receiving an educational handout on CMV infection in pregnancy. Pre- and post- education questionnaires were utilized to assess knowledge. Pregnant women less than 34 weeks gestation were eligible. 263 women were enrolled and 215 women completed both questionnaires. Prior to education, 33% of pregnant women surveyed had heard of CMV. This increased to 75% after the educational handout was administered. Each of the recommended hygiene practices was assigned a favorability score between 1-5 (5 is the most favorable) and each recommended hygiene practice had an average favorability score between 4-5. 74% of participants reported increasing hygiene practices after education. 96% of participants indicated they were happy to have received the education. 98% thought more women should receive this education during prenatal care. Pregnant women viewed education about CMV infection favorably and subsequently increased the frequency of the recommended hygiene practices. Introducing and educational handout to routine prenatal care may be beneficial in increasing awareness of CMV infection in pregnancy.

Prenatal infection with Mycoplasma pulmonis in rats exaggerates the angiotensin II pressor response in adult offspring.

Exposure to different stressors in utero is linked to adult diseases such as obesity and hypertension. In this study, the impact of prenatal infection (PNI) on adult body weight and cardiovascular function was evaluated using a naturally occurring rodent pathogen, Mycoplasma pulmonis (MP). Pregnant Sprague-Dawley rats were infected with MP on gestationalday 14 and gave birth naturally. Adult PNI offspring weighed more than controls, but resting mean arterial pressure (MAP) was unchanged. Subcutaneous injection of angiotensin II (10 μg/kg) elicited a rise in MAP that was greater in both male and female PNI offspring compared with controls (P < 0.03). The accompanying reflex bradycardia was similar to the controls, suggesting that PNI induced baroreflex dysfunction. Subcutaneous nicotine administration, a potent cardiorespiratory stimulus, also elicited a transient rise in MAP that was generally greater in the PNI group, but the change in MAP from baseline was only significant in the PNI females compared with controls (P < 0.03). Elevated body weight and cardiovascular reactivity in the PNI offspring was associated with an increase in the ratio of hypothalamic corticotrophin-releasing hormone receptors type 1 to type 2 gene expression in both sexes compared with controls. These findings support previous studies demonstrating that PNI induces alterations in cardiovascular function and body weight. Yet, unlike previous studies utilizing other models of PNI (e.g., endotoxin), MP PNI did not induce resting hypertension. Thus, our study provides a foundation for future studies evaluating the cardiovascular risks of offspring exposed to microbial challenges in utero.

Effects of prenatal bacterial infection on cognitive performance in early childhood.

Previous epidemiologic studies have reported adverse neurodevelopmental sequelae following prenatal infectious exposure, yet long-term effects estimated from these observational studies are often subject to biases due to confounding and loss to follow-up. We demonstrate the joint use of inverse probability (IP) treatment and censoring weights when evaluating neurotoxic effects of prenatal bacterial infection. We applied IP weighting for both treatment and censoring to estimate the effects of maternal bacterial infection during pregnancy on mean intelligence quotient (IQ) scores measured at age 7 using the Wechsler Intelligence Scale for Children. Participants were members of a population-based pregnancy cohort recruited in the Boston and Providence sites of the Collaborative Perinatal Project between 1959 and 1966 (n=11984). We calculated average treatment effects (ATE) and average treatment effects on the treated (ATT) using IP weights estimated via generalized boosted models. ATE- and ATT-weighted mean IQ scores were lowest among offspring exposed to multi-systemic bacterial infection during pregnancy and highest for those unexposed. The effects of prenatal bacterial infection were greater among male offspring, particularly on performance IQ scores. Offspring who were exposed to multi-systemic bacterial infection in the third trimester displayed the largest reduction in mean full-scale, verbal, and performance IQ scores at age 7 compared to those unexposed or exposed in earlier trimesters. We find that prenatal bacterial infection is associated with cognitive impairments at age 7. Associations are strongest for more severe infections, that occur in the third trimester, and among males. Public health intervention targeting bacterial infection in pregnant women may help enhance the cognitive development of offspring.

Normal Hearing Function in Children Prenatally Exposed to Zika Virus.

Introduction The association between prenatal Zika virus infection and hearing alterations in offspring has been the object of some studies, although few have assessed children without microcephaly. However, a current trend to include prenatal Zika virus exposure in the group of risk indicators for hearing loss is noted. Objective To present a series of 27 children prenatally exposed to the Zika virus submitted to multiple hearing assessments over time. Methods A cohort of children born to symptomatic mothers with laboratorial Zika virus infection confirmation during pregnancy was submitted to an otoacoustic emission test, auditory brainstem response test (automated, neurodiagnostic and frequency-specific), audiometry, and imitanciometry over a period of 36 months since birth. The hearing assessment was performed independently of the presence of microcephaly or other apparent signs of congenital Zika syndrome. Results The hearing tests presented predominantly normal results. Some children had signs of middle ear pathology. The only microcephalic child had normal electrophysiological tests, as well as preserved audiometric thresholds, but presented altered motor responses to sound. Conclusion Prenatal exposure to Zika virus does not always determine hearing impairment. This risk seems to be more associated to the severity of the central nervous system damage. Hearing screening and follow-ups of the affected children are important, as well as further research in this area.

Cost-effectiveness of Prophylactic Zika Virus Vaccine in the Americas.

Zika virus remains a major public health concern because of its association with microcephaly and other neurologic disorders in newborns. A prophylactic vaccine has the potential to reduce disease incidence and eliminate birth defects resulting from prenatal Zika virus infection in future outbreaks. We evaluated the cost-effectiveness of a Zika vaccine candidate, assuming a protection efficacy of 60%–90%, for 18 countries in the Americas affected by the 2015–2017 Zika virus outbreaks. Encapsulating the demographics of these countries in an agent-based model, our results show that vaccinating women of reproductive age would be very cost-effective for sufficiently low (<$16) vaccination costs per recipient, depending on the country-specific Zika attack rate. In all countries studied, the median reduction of microcephaly was >75% with vaccination. These findings indicate that targeted vaccination of women of reproductive age is a noteworthy preventive measure for mitigating the effects of Zika virus infection in future outbreaks.

Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress

Prenatal infections are environmental risk factors for neurodevelopmental disorders. In addition, traumatic experiences during adolescence in individuals exposed to infections during gestation could increase the risk of schizophrenia. It is of the most crucial importance to discover potential markers of the disease in its early stages or before its onset, so that therapeutic strategies may be implemented. In the present study, we combined a proposed two-hit model of schizophrenia-related symptoms with proton magnetic resonance spectroscopy (1H-MRS) to discover potential biomarkers. To this end, we i.p. injected 100 μg/kg/ml of lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to five episodes of stress or handling on alternate days during postnatal days (PND) 28–38. Once the animals reached adulthood (PND70), we evaluated prepulse inhibition (PPI). At PND90, we performed an ex vivo 1H-MRS study in the cortex and striatum. While we did not detect alterations in PPI at the age tested, we found neurochemical disturbances induced by LPS, stress or (more interestingly) their interaction. LPS decreased glucose levels in the cortex and striatum and altered glutamate, glutamine and N-acetylaspartate levels. Glutamate and glutamine levels in the left (but not right) striatum were differentially affected by prenatal LPS exposure in a manner that depended on stress experiences. These results suggest that alterations in the glutamate cycle in the striatum could be used as early markers of developmental disorders.

Toxoplasmosis in pregnancy: a neglected bane but a serious threat in Nigeria.

Toxoplasmosis is a global health threat in which occurrence in pregnant women poses grave consequences to fetal wellbeing. Studies on prenatal Toxoplasma gondii infection are generally limited in sub-Saharan African countries, including Nigeria. The risk of transmission of toxoplasmosis is very high in Nigeria due to the favourable climatic conditions and prevailing behavioural and socio-economic factors that could aid transmission. Currently, there are no systematic and organized procedures for diagnosis and treatment of maternal toxoplasmosis in Nigeria. These conditions forecast possible unabated transmission in many areas and exponential impact on associated adverse events of the disease during pregnancy. This paper highlights the importance of early diagnosis and treatment during pregnancy which may forestall subsequent development of infection in children delivered by infected mothers. Inclusion of toxoplasmosis control policy in the routine antenatal care of pregnant women is therefore strongly recommended.