This review will focus on the effects of viral infections in pregnancy. Throughout gestation, viral infections are known to lead to adverse events including mortality of the fetus and mother, premature birth, miscarriage and congenital anomalies. The intricate immunological environment of pregnancy requires a fine balance in which the placenta must accept exposure to some allogeneic fetus while protecting against pathogens. Even though natural defense in the maternal-fetal interface prevents viral transmission, some viruses hijack poorly understood mechanisms that disrupt the integrity of the placenta, leading to vertical transmission and this can have severe consequences on fetal health. This review highlights the intricate relation of main viruses with pregnancy, including mechanisms in pathogenesis as well as maternal-fetal complications, and the cell and molecular substrate for trans placental infection. Key features of placental immune protection are trophoblast cells, innate immune populations, cytokine control, pathogen recognition and antimicrobial products, all being essential in preparing for new emerging challenges to the pregnant population.

BackgroundTuberculosis (TB) poses a significant risk during pregnancy and the postpartum period, with evidence linking these stages to an increased likelihood of progression from latent TB infection to active disease. Although TB has been associated with adverse pregnancy outcomes, including congenital transmission, the mechanisms by which Mycobacterium tuberculosis (Mtb) affects placental structure and function remain poorly understood.ObjectiveThis study aimed to investigate the stage-dependent effects of Mtb infection on human placental tissue and assess the potential for vertical transmission using an ex vivo placental infection model.MethodsHuman term placental explants were infected ex vivo with Mtb H37Rv in logarithmic (log) phase and in reactivated dormancy phases (rNRP1 and rNRP2). Bacterial viability was evaluated by CFU quantification at 4, 24, and 48 h post-infection. Histological changes were assessed with hematoxylin-eosin staining; bacilli were visualized using Kinyoun staining and immunofluorescence. Cytokine secretion was measured via multiplex ELISA assays, and Mtb gene expression was analyzed by RT-qPCR.ResultsMtb in rNRP1 and rNRP2 phases replicated efficiently within placental explants, with CFU increasing by more than one log at 48 h. rNRP2 exhibited delayed tissue entry (only 4% at 24 h), suggesting distinct virulence dynamics based on bacterial phase. Both reactivated phases induced villitis, stromal fibrosis, and reduced vascular integrity, with rNRP2 causing the most severe tissue damage. rpfB was significantly upregulated during reactivation (14-fold in rNRP1, 7-fold in rNRP2 at 24 h). Dormancy genes (dosR, hspX, icl1) and stress-response markers (sigH, whiB3), were over-expressed in rNRP1, suggesting Mtb remain metabolically equipped to withstand host stresses during early reactivation. Cytokine analysis revealed lower pro-inflammatory responses in rNRP1-infected tissue, while rNRP2 and log-phase Mtb triggered stronger metalloproteinase activity.ConclusionMtb can infect, persist, and replicate within human placental tissue, compromising its structural and immune integrity. These effects vary with the bacterial physiological phase, with early-reactivated Mtb showing the greatest capacity for tissue dissemination and damage. These findings underscore a dual risk of placental injury and increased potential for vertical transmission during early reactivation, emphasizing the need for timely TB screening and intervention during pregnancy.

The protozoan parasite Toxoplasma gondii causes severe pathologies in the infected fetus following vertical transmission during pregnancy. Primary T. gondii infection increases the risk of miscarriage during the first trimester of gestation; however, the cellular and molecular mechanisms are not fully understood. Extravillous trophoblasts (EVTs) are fetal cells that migrate and invade the maternal decidua to allow placenta formation and embryo implantation. The transcription factors Forkhead box O3a (FOXO3a) and FOXO1 play a central role in the regulation of EVT migration and invasion. Hence, impairment of EVT functions is associated with FOXO3a/FOXO1 dysregulation and poor pregnancy outcomes. Interestingly, T. gondii-driven inactivation of FOXO3a and FOXO1 was reported in fibroblasts and macrophages. Using a combination of cell imaging, reverse genetics and biochemical approaches in the human trophoblast cell line HTR-8/SVneo, herein we provide evidence that infection with type I RH T. gondii strain inhibits invasiveness and migratory activities in EVTs by repressing FOXO3a-and FOXO1-dependent and independent gene expression. Indeed, either T. gondii infection or single knockdown of FOXO3a and FOXO1 reduced invasion and migration properties in EVTs. Selective chemical blockade of parasite motility and host cell entry indicates that active infection is indispensable for reduced EVT migration but is only partially required for T. gondii-driven repression of EVT invasiveness. Mechanistically, T. gondii infection led to AKT-sensitive phosphorylation and nuclear exclusion of FOXO3a and FOXO1 in EVTs. An RT-qPCR-based screening identified a subset of invasion-and migration-associated genes downregulated in T. gondii-infected EVTs (MMP2, MMP3, MMP14, TIMP2, MUC1, and ITGB3). Transcription of genes encoding MMP3 and integrin β3 decreased in FOXO3a KD and FOXO1 KD EVT cell lines, respectively. These data along with pharmacological inhibition of AKT in infected cells provide evidence that T. gondii downregulates MMP3 and ITGB3 gene expression in EVTs in an AKT-FOXO3a/FOXO1-dependent fashion. In all, we have uncovered a novel regulatory mechanism involved in the repression of EVT migration and invasion properties during T. gondii infection. Further investigation using in vivo and ex vivo models of placental infection is required to determine whether T. gondii-driven dysregulation of EVT functions contributes to pregnancy complications associated with congenital toxoplasmosis.

ABSTRACT The placenta possesses several structural and immunological barriers against viral infections, the SARS-CoV-2 detection in placental tissues has raised concerns regarding possible alternative viral entry mechanisms beyond the canonical ACE2/TMPRSS2-mediated pathway. In this context, the present study evaluated the immunohistochemical expression patterns of ADAM17, Cathepsin L, Clathrin, ACE-2, Furin, NRP-1, and TMPRSS2—molecules involved in SARS-CoV-2 placental entry pathways – as well as the detection of viral RNA by RT-qPCR in paraffin-embedded samples. The study included 75 paraffin-embedded placental samples (decidua and villi) collected after spontaneous placental delivery at birth from patients who tested positive for COVID-19 (COVID-19 Group), and 19 paraffin-embedded control placental samples collected prior to the COVID-19 pandemic (NON-COVID-19 Group). A statistically significant reduction in NRP-1 expression was observed in the COVID-19 group decidua (p < 0.001), including in RT-qPCR – positive samples (p = 0.001), regardless of comorbidities or underlying conditions. A statistically significant reduction in Clathrin expression was also found in the decidual samples of the COVID-19 group and in RT-qPCR – positive samples (p = 0.05and 0.013, respectively), while Cathepsin L expression was significantly increased in the placental villi of the COVID-19 group (p < 0.001) and in RT-qPCR – positive samples (p = 0.005). These findings may contribute to a better understanding of the mechanisms underlying SARS-CoV-2 interaction with the placenta, possibly through auxiliary and/or endocytic entry pathways, and may support future investigations into the impact of these alterations in the context of maternal SARS-CoV-2 infection.

Postmortem analysis of the causes of perinatal calf mortality on dairy farms.

Background: Placental infections caused by Schistosoma spp. and sexually transmitted microorganisms can adversely impact pregnancy outcomes. However, the association between molecular detection of these pathogens in placental tissue and corresponding histopathological inflammation remains unclear, particularly in sub-Saharan African populations. Methods: In this cross-sectional study, placental parenchyma specimens with limited membrane sampling were collected from 103 Ivorian and Ghanaian mothers without known pregnancy or birth complications. Tissue pieces adjacent to PCR-tested samples were analyzed by real-time PCR targeting Chlamydia trachomatis, Mycoplasma hominis, Neisseria gonorrhoeae, Schistosoma spp., Streptococcus agalactiae, Trichomonas vaginalis, Ureaplasma parvum and Ureaplasma urealyticum. Corresponding adjacent tissues were examined by routine histopathology, supplemented with immunohistochemistry when higher pathogen DNA quantities were detected, to assess inflammatory changes. Results: Real-time PCR detected U. urealyticum in 15 out of 103 cases (14.6%, ±0.7%), U. parvum in 13 (12.6%, ±0.6%), S. agalactiae in 11 (10.7%, ±0.5%), the S. haematobium complex in four (3.9%, ±0.2%), M. hominis in four (3.9%, ±0.2%), confirmed N. gonorrhoeae in two (1.9%, ±0.1%) and non-confirmed N. gonorrhoeae in one (1.0%, ±0.1%), T. vaginalis in two (1.9%, ±0.1%), and C. trachomatis (non-lymphogranuloma venereum serovar) in one (1.0%, ±0.1%). Overall, pathogen DNA levels were low, with only four positive PCR results yielding cycle threshold (Ct) values below 30 and none below 25. Histopathological examination revealed no relevant inflammatory changes in any samples. Conclusions: Placental parenchyma tissues with limited membrane sampling testing positive for Schistosoma spp. or sexually transmitted pathogens by molecular methods demonstrated no corresponding histopathological inflammation. These findings warrant confirmatory studies to better characterize potential region-specific placental infection phenotypes and their clinical significance.

SUMMARYZika virus (ZIKV) can be vertically transmitted from a pregnant mother to the developing fetus, resulting in microcephaly and/or other congenital malformations. Dengue virus (DENV) cross-reactive antibodies can facilitate ZIKV placental transcytosis and enhance ZIKV infection of placenta macrophage-Hofbauer cells through binding to Fc-γ receptors (FcγRs). To understand the role of individual FcγR in antibody-mediated ZIKV placental infection, we generated a comprehensive panel of Fc-variants spanning a wide range of binding affinities to different FcγRs. We found that mutations with increased affinity to FcγRI strongly correlated with an increased frequency of infected pro-monocytic U937 and Hofbauer cells. Next, we genetically deleted individual FcγR in U937 cells, and found that the knockout of FCGR1A gene completely abolished ZIKV infection. In contrast, the deletion of FCGR2B gene showed no effect on ZIKV infection, and the deletion of FCGR2A gene had only a moderate impact on ZIKV infection. We further observed that FcγRI was involved in both increased ZIKV internalization and replication. Collectively, our results establish FcγRI as the key Fc receptor responsible for antibody-mediated ZIKV infection in both U937 and primary placental macrophages. These mechanistic findings not only provide insight into the importance of FcγRI in ZIKV vertical transmission but also highlight FcγRI as a potential therapeutic target, with significant implications for the development of strategies to prevent ZIKV transmission from mother to fetus.

Protocol for a human placental explant model to study acute responses to pathogens

The guinea pig as a relevant preclinical model in the rat race for a vaccine against congenital cytomegalovirus infection.

A method for ex vivo human placental Listeria monocytogenes infections.

Glucocorticoids are steroid hormones that regulate multiple physiological processes throughout the lifespan and play a central role in the adaptive stress response. Their biological effects are mediated by the glucocorticoid receptor, which acts through both genomic and nongenomic mechanisms to regulate transcriptional signatures and intracellular signaling pathways, respectively. These effects are tissue- and context-dependent, allowing the body to adapt to developmental and environmental changes. Glucocorticoid-mediated effects are influenced by both hormone bioavailability and tissue-specific responsiveness. Reduced glucocorticoid sensitivity has been observed in patients with severe disease or a diminished response to synthetic glucocorticoid therapies. During the perinatal period, the endogenous glucocorticoid cortisol exerts unique developmental effects on the late-gestation fetus that are essential for extrauterine life. Antenatal glucocorticoid therapy has demonstrated beneficial effects in preventing prematurity-related diseases, while postnatal glucocorticoid treatment reduces inflammation and improves oxygenation in bronchopulmonary dysplasia. However, these therapies exhibit variable responses, both in terms of their beneficial and adverse effects. Furthermore, preterm newborns are exposed to adverse intrauterine environments, including placental insufficiency and infection, which-when combined with immaturity-result in dysregulated perinatal glucocorticoid homeostasis. Intrauterine stressors can therefore alter fetal glucocorticoid sensitivity, partially explaining the variability in clinical outcomes observed among preterm newborns. These adverse conditions may also interact with genetic and physiological factors, such as gestational age and fetal sex, further amplifying glucocorticoid homeostasis dysregulation. In this review, we explore the clinical and basic science evidence on the endogenous determinants of perinatal glucocorticoid sensitivity, with an emphasis on their clinical implications for disease risk and the efficacy of glucocorticoid therapy in the preterm newborn.

Pregnant women in sub-Saharan Africa face heightened susceptibility to Plasmodium falciparum malaria, with placental sequestration driving adverse outcomes. The infection may lead to pregnancy-associated malaria (PAM) because of the sequestration of Plasmodium falciparum-infected erythrocytes in the placental intervillous space. Although there are several tools for diagnosing malaria infection during pregnancy, including blood smear microscopic examination, rapid diagnostic tests, and PCR, there are no tools for detecting placental infection and, by extension, any dysfunction associated with PAM. Thus, PAM, specifically placental infection, can only be confirmed via postnatal placental histopathology. Therefore, there is an urgent need for specific plasma biomarkers of PAM. Here, we used the high throughput proximity extension assay to screen plasma from malaria-exposed pregnant women for differentially expressed proteins that may serve as candidate biomarkers of Plasmodium falciparum infection during pregnancy, with future potential to inform diagnosis of PAM or adverse malaria outcomes. Such biomarkers may also elucidate the pathophysiology of PAM. Using proximity extension assay (PEA), we identified elevated IgG Fc receptor IIb (FCGR2B) and heme oxygenase-1 (HO-1) in malaria-positive pregnancies, while neurturin (NRTN) and IL-20 were downregulated. IL-20 emerged as a top candidate biomarker, warranting validation in large cohorts with placental histopathology.

The discovery that the Oropouche virus (OROV) can be transmitted vertically from an infected pregnant mother to the fetus, resulting in fetal and placental OROV infection, miscarriage, stillbirth, and congenital malformations including microcephaly, has emphasized its public health significance. Because of the importance of breastfeeding in those areas affected by the Oropouche fever outbreak, public health agencies have continued to encourage nursing among mothers who have had OROV infection or who reside or travel in endemic regions. However, the basis for this recommendation has not been stated. At the present time, there have been no reports of the OROV being transmitted from mothers having had Oropouche fever during pregnancy to their infants through breast milk. To further evaluate the potential risk of OROV transmission through breastfeeding, we have examined the peer-reviewed literature to determine if related Orthobunyavirus species infecting humans and animals are transmissible via breast milk. Bibliographic search engines, including PubMed, Scopus, and Google Scholar, were extensively reviewed using keywords, MeSH terms, and other sources cited in the articles examined. Studies investigating Orthobunyavirus species that infect humans and animals, including reassortant strains of OROV and viruses within the Simbu serogroup, were reviewed. We found that there have been no reported events of vertical transmission of any Orthobunyavirus through breast milk. Based on these results, we believe that the advantages of breastfeeding following maternal OROV infection outweigh any negligible risk for vertical transmission.

Placental Privilege: Evidence of organ resilience in severe COVID-19 in pregnancy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) cause placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro. Trophoblast exposure to EVs isolated from patients with an active infection (AI), but not controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an AI, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19, depending on the gestational timing of infection, and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs, and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.

The COVID-19 pandemic presents several challenges during pregnancy including thromboembolic complications, direct placental infection, transplacental transmission, and systemic hyperinflammatory state. The liver is the second most commonly affected organ in SARS-CoV-2 infection after the lungs. Mechanisms of liver injury in COVID-19 patients can include: direct viral cytopathic effect, worsening of underlying liver disease, cytokine storm, hypoxic ischemic injury, and cholangiopathy leading to persistent marked cholestasis. Here we describe 3 infants at Texas Children's Hospital with perinatal SARS-CoV-2 exposure with persistent cholestasis and histologic evidence of extrahepatic biliary obstruction suggesting underlying biliary atresia (BA) with some atypical features possibly exacerbated by SARS-CoV-2 infection. All 3 patients described in this case series developed liver failure in the setting of low GGT cholestasis, and all 3 required liver transplantation within the first year of life. Though post-COVID cholangiopathy is described in adults in the literature, none of the infants in our series had moderate or severe COVID infection but still progressed to advanced liver disease. Instead it is very likely that the patients in our series had underlying BA with some atypical features, with the commonality of having been exposed perinatally to SARS-CoV-2 Though further studies are needed to determine causality, our case series raises the question of if the timing of exposure/infection plays a role in prognosis.

Introduction: Group B Streptococcus (GBS) colonization leads to placental infection and inflammation, known as chorioamnionitis (CA). Fetal exposure to CA is linked to elevated risks of neurobehavioral impairments in offspring, including autism spectrum disorder, which is more prominent in males than females. In our preclinical model of GBS-induced CA, males exhibited heightened placental inflammation compared to females, correlating with more severe subsequent neurobehavioral impairments. We hypothesize that androgens upregulate the placental immune response in male fetuses, potentially contributing to GBS-induced autistic-like traits in male offspring. Our previous findings demonstrated that there were reduced pro-inflammatory cytokines and polymorphonuclear cell infiltration in flutamide (androgen receptor antagonist) plus GBS-infected compared to vehicle plus GBS-infected placenta. In this study, we investigated the effect of end gestational androgen blockade on brain injury patterns and neurobehavioral outcomes in offspring in utero exposed to GBS CA. Methods: Lewis dams received daily injections of vehicle or flutamide from gestational day (G) 18–21, followed by saline or inactivated GBS injections from G19 to 21. Behavioral assessments were conducted from postnatal day (P) 9–40 and brains were dissected on P50. Results: Behavioral assessments revealed impaired social interactions in CA-exposed versus unexposed male rats. These impairments were not observed in flutamide-treated rats. Histological analysis of forebrains at P50 showed lateral forebrain ventricle enlargement and reduced periventricular white matter thickness, namely the corpus callosum and external capsule in offspring exposed to CA contrasting with an improvement in these outcomes observed in flutamide treated rats. Exposure to CA reduced the density of CC-1+ oligodendrocytes in the external capsule whereas flutamide mitigated this reduction in offspring at P50. Conclusion: These findings suggest a significant role for androgens in the skewed sex ratio observed in developmental impairments resulting from perinatal inflammation, underscoring the need for personalized sex-specific neuroprotective therapies.

To evaluate the presence and levels of cytomegalovirus (CMV) cell-free DNA (cfDNA) fragments in women pregnant with a fetus with symptomatic congenital CMV (cCMV). The study comprised nine women whose fetuses were diagnosed with cCMV between June 2019 and July 2024 at 20 + 4 to 34 + 1 weeks' gestation (n = 8) or neonatally (n = 1) after primary or non-primary maternal infection. In eight women, cfDNA sequencing data from a single timepoint were analyzed, either retrospectively, on data generated from 11-13 weeks' gestation (n = 5) or prospectively, on data generated from 20-26 weeks' gestation (n = 3), upon the diagnosis of cCMV. In one woman (Case 6), CMV-cfDNA analysis was performed at four timepoints: at 12 + 5 weeks (routine non-invasive prenatal testing); 23 + 3 weeks (cCMV diagnosis); and 30 min and 12 h after termination of pregnancy (TOP) at 23 + 6 weeks. CMV-cfDNA was detectable in all cases. Mostly low levels of CMV-cfDNA were observed in samples obtained at 11-13 weeks' gestation and consistently high levels of CMV-cfDNA were present in samples obtained at cCMV diagnosis. In Case 6, the level of maternal CMV-cfDNA decreased substantially in the samples tested after TOP, compared with samples obtained before TOP. Low levels of CMV-cfDNA detected between 11 and 13 weeks may be a biomarker for severe fetal cCMV. CMV-cfDNA analysis in the first trimester could be of added value in CMV screening, particularly for non-primary maternal infections that cannot be identified using other methods. However, as CMV-cfDNA is detectable in many pregnant women in the first trimester, further studies are needed to determine the predictive value of CMV-cfDNA as a biomarker for the development of severe fetal cCMV. High levels of CMV-cfDNA at fetal cCMV diagnosis and low levels directly after TOP suggest that the level of CMV-cfDNA in maternal plasma may not necessarily reflect an active maternal infection, but could indicate a placental infection. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Lactococci have been associated with fetal and neonatal infections in humans and cattle. Here we describe a case of reproductive loss attributed to Lactococcus petauri in a lemur. A full-term black-and-white ruffed lemur (Varecia variegata) was found dead in the indoor area of a zoologic exhibit. Classification as a late-term abortion or stillbirth was unclear as the precise gestational time was unknown. A medical checkup of the dam revealed fever and neutrophilic leukocytosis; recovery followed treatment with enrofloxacin. The main histologic findings were placental edema and hemorrhage, hepatic necrosis, desquamated amniotic epithelial cells in alveoli, and subendocardial and myocardial hemorrhages. Tissue Gram stain revealed abundant gram-positive cocci arranged in short chains in the placenta and liver. Toxoplasma gondii was not detected by immunohistochemistry. Bacterial isolates from the placenta and fetal liver were identified as Lactococcus garvieae by MALDI-TOF MS. However, the isolates were found to be L. petauri by determining their in-silico DNA-DNA hybridization and average nucleotide identity values using pairwise comparisons of their whole-genome sequences and the genomes of the type strains. The antimicrobial susceptibility of isolates by the disk diffusion method revealed resistance to tylosin, gentamicin, apramycin, neomycin, amikacin, ampicillin, and florfenicol. We attributed the reproductive loss in this lemur to placental and fetal infection by L. petauri.

Macrophages play a crucial immunological role in maintaining pregnancy. Placental malaria infection may cause dysfunction in decidual macrophages which then culminates in the associated pregnancy complications. Here, we determined the influence of placental malaria on decidual macrophages, by assessing their distribution based on their unique phenotypes, and examining their expression levels of transcription factors as well as angiogenic factors, in placentas from women living in a malaria-endemic area. We compared these macrophage parameters in placentas from malaria infected women to those from the uninfected women. Placentas were collected upon delivery and malaria infection determined by histology together with PCR from dry blood spots obtained from placental blood. Following enzymatic dissociation of placental tissue, immune cells were enriched from the total population of placental cells by density centrifugation. Macrophage phenotypic characteristics were then analyzed from the placental immune cells by flow cytometry. The expression of surface markers CD68, CD80, CD86, CD163, CD206, and CD209, was used to delineate the macrophage populations. For gene expression profiling, macrophages were isolated from the placental immune cells and the expression level of transcription factors STAT-1, IRF-5, STAT-6, c-Maf and angiogenic factors ANG-1, ANG-2 and VEGF determined by qPCR. We found no difference in the total macrophage populations and M1 and M2 macrophage profiles between uninfected and infected placentas, however, M2 macrophages were significantly higher compared to their M1 counterparts regardless of infection status. Notably, the gene expression levels of the transcription factor STAT-6 and angiogenic factor ANG-1 were significantly lower in infected placentas. These findings provide a basis for further understanding of the role of placental macrophages in placental malaria pathogenesis. Analysis of the functional consequences of these observations is needed to determine if these factors can be explored to reprogram macrophage polarization to desired state.