Erica L. Johnson

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide, with limited tools for early prediction or targeted prevention. Increasing evidence identifies the placenta as a central regulator of gestational duration, and alterations in placental gene regulatory programs have been associated with PTB. This review synthesizes recent advances in placental genomics and epigenomics, emphasizing how cell-type-specific regulatory landscapes shape PTB risk. We describe how DNA methylation, chromatin accessibility, and transcriptional heterogeneity across trophoblasts, Hofbauer cells, endothelial cells, Natural Killer (NK) cells, and mesenchymal stromal cells integrate maternal, fetal, immune, and environmental signals. We further evaluate emerging liquid biopsy approaches, focusing on circulating cell-free placental DNA (cfpDNA) methylation as a minimally invasive strategy to detect placental dysfunction. Single-cell and long-read sequencing technologies have enabled high-resolution mapping of placental regulatory architecture, revealing cell-type-specific pathways underlying inflammation, impaired trophoblast differentiation, and aberrant vascular remodeling. These studies support the investigation of placental epigenetic alterations as potential contributors to PTB-associated biology, although their causal roles and consistency across PTB subtypes remain uncertain. Circulating cfpDNA methylation profiles are being investigated as minimally invasive indicators of placental biology, but their accuracy and clinical utility for PTB prediction require further validation. Together, these findings suggest that epigenomic alterations may be associated with biological pathways implicated in PTB and may also provide measurable molecular signatures in maternal circulation.

Introduction: Elevated maternal body mass index (BMI) during pregnancy is associated with adverse maternal and offspring outcomes; yet the molecular pathways linking maternal metabolic status to placental function and fetal immune development remain poorly understood. Methods: We performed multi-compartment transcriptomic profiling across the maternal–placental–fetal axis, complemented by exploratory cytokine profiling in a larger available plasma sample set. Maternal peripheral blood mononuclear cells (PBMCs), placental villous tissue, cord blood mononuclear cells (CBMCs), maternal plasma, and cord plasma were collected at delivery when available. RNA-seq data were available for 17 maternal PBMC samples, 18 CBMC samples, and 14 placental samples from 20 term pregnancies, while Luminex profiling was performed in 31 maternal plasma and 31 cord plasma samples, comprising available plasma from the RNA-seq cohort plus additional plasma-only samples. RNA-seq analyses were performed separately within each compartment using third-trimester BMI as a continuous variable, followed by Hallmark pathway enrichment, co-expression network analysis, cytokine/chemokine profiling and targeted placental qRT-PCR validation. Results: Higher maternal third-trimester BMI was associated with distinct transcriptional programs across maternal, placental, and fetal compartments. In maternal PBMCs, higher third-trimester BMI was associated with a modest but coordinated gene-level signature and pathway patterns consistent with selective immune activation, alongside broader attenuation of metabolic, inflammatory, and redox-related programs. Placental tissue exhibited the strongest BMI-associated transcriptomic signature, characterized by metabolic and stress-response activation, including enrichment of oxidative phosphorylation, reactive oxygen species signaling, unfolded protein response, DNA repair, MTORC1 signaling, and adipogenesis. Exploratory co-expression analyses further highlighted candidate extracellular matrix, vascular-interface, and placental endocrine-associated modules. In CBMCs, higher third-trimester BMI was associated with fetal immune-developmental remodeling, including proliferative pathway enrichment and relative attenuation of inflammatory and immune-response signaling. Exploratory plasma cytokine profiling identified nominal compartment-specific associations with higher third-trimester BMI; however, none remained significant after multiple-testing correction. Discussion: Collectively, the multi-compartment findings nominate candidate mitochondrial, inflammatory, vascular-interface, extracellular matrix, and placental endocrine-associated pathways for validation in larger independent cohorts.

Melatonin regulates inflammation and oxidative stress at the placenta, but its effects on specific placental cell types remain unclear. This study investigated how melatonin influences inflammatory and oxidative stress responses, cytokine secretion, NRF2-associated antioxidant responses, and transcriptomic responses in JEG-3 trophoblast-like cells and primary decidual macrophages exposed to lipopolysaccharide (LPS). Melatonin reduced LPS-induced inflammatory cytokine production and intracellular reactive oxygen species accumulation, with pretreatment producing the strongest anti-inflammatory effects. Although NLRP3 transcript expression differed according to treatment sequence, melatonin was associated with reduced inflammatory cytokine secretion despite limited changes in total NLRP3 protein expression. Melatonin also differentially influenced antioxidant responses across placental cell types, with decidual macrophages exhibiting broader functional and transcriptional changes than JEG-3 trophoblast-like cells. Transcriptomic profiling revealed dose- and cell type-dependent effects, with decidual macrophages exhibiting altered expression of genes and pathways associated with inflammatory signaling, oxidative phosphorylation, and reactive oxygen species regulation. In contrast, JEG-3 trophoblast-like cells demonstrated limited transcriptional remodeling and more modest engagement of inflammatory signaling pathways than primary decidual macrophages. These findings suggest that melatonin differentially modulates inflammatory and oxidative stress responses across placental cell types at the maternal-fetal interface. Collectively, these data support the potential role of melatonin in promoting placental redox-inflammatory balance during inflammatory stress and provide a foundation for future studies in physiologically relevant models.

Background/Objectives: Food insecurity (FI) affects a substantial proportion of pregnant individuals in the United States and varies across geographic contexts. Rural and urban communities differ in food access, socioeconomic conditions, and environmental exposures, yet how these differences relate to maternal biology remain misunderstood. Methods: This study examined associations between FI, geographic context, and metabolic, nutritional, and inflammatory biomarkers among pregnant participants in the Southeastern United States (SE-US) using data from the All of Us (AoU) Research Program. Survey, clinical, and laboratory data were integrated with ZIP3-level geographic and food environment indicators. Analyses were conducted using biomarker-specific complete-case cohorts and multivariable regression models. Results: This study found that FI was more prevalent among rural participants than urban participants. However, in the overall cohort, FI was associated with higher body mass index, higher non-fasting glucose, higher C-reactive protein, and lower high-density lipoprotein cholesterol. Pregnant food-insecure participants also exhibited lower concentrations of vitamin B12, albumin, vitamin D, and folate, while ferritin did not differ. Stratified analyses demonstrated variability in these associations by urbanicity, with stronger and more consistent differences observed in urban populations and fewer significant differences in rural settings. Conclusions: Limitations of this study include potential residual confounding, EHR-related selection bias, exposure misclassification, and limited generalizability. Despite the limitations, recent self-reported household FI, assessed at enrollment and referring to the preceding 12 months, was associated with differences in several metabolic and nutritional biomarkers, with patterns varying by geographic context. Further longitudinal research is needed to clarify these associations and inform targeted interventions.

Review objectives: This scoping review aims to map the extent and nature of digital, biomarker, and multi-omics evidence on stress and cardiometabolic health trajectories among women in Sub-Saharan Africa, with particular attention to hypertension, glycemic and diabetes-related outcomes, adiposity and obesity, dyslipidemia, metabolic syndrome, pregnancy-related cardiometabolic conditions, and cardiovascular sequelae. In addition, the review will consider patterns of vulnerability and potential indicators of cardiometabolic resilience, defined broadly as the capacity to maintain or regain health despite exposure to stressors, where these are explicitly examined or can be inferred from study findings. Cardiometabolic markers are being captured alongside real-time physiological and behavioral data through digital tools and wearable technologies, providing opportunities for early detection, continuous monitoring, and risk stratification of cardiometabolic disorders (CMDs). The review will further assess the degree of integration across these domains, while identifying key research gaps and emerging methodological trends. Methods: The review will follow the Joanna Briggs Institute methodology for scoping reviews and will be reported in accordance with the PRISMA extension for Scoping Reviews. A comprehensive search will be conducted across electronic databases, including MEDLINE (PubMed), Embase, Scopus, Web of Science Core Collection, CINAHL, PsycINFO, Global Index Medicus, the Cochrane Library, and IEEE Xplore, as well as grey literature sources such as Google Scholar, World Health Organization Institutional Repository for Information Sharing, and the World Bank Open Knowledge Repository using pre-specified Boolean operators and keywords. Studies published in English from January 2015 to the date involving women aged 18 years and above in Sub-Saharan Africa that examine stress in relation to cardiometabolic outcomes using digital, biomarker, and/or multi-omics approaches will be included. Findings will be synthesized descriptively, with evidence stratified by cardiometabolic domain where feasible, including blood pressure and hypertension, glycemic and diabetes-related outcomes, adiposity and obesity, lipid-related outcomes, pregnancy-related cardiometabolic conditions, and broader cardiovascular outcomes.

Background: Hofbauer cells are fetal macrophages in the placental villous core that contribute to maternal–fetal tolerance and antiviral defense, but how their immune programs change across gestation in response to viral exposure remains poorly understood. Methods: Primary Hofbauer cells were isolated from early- to mid-gestation and term human placentas and exposed in vitro for 24 h to HIV-1 or cytomegalovirus (CMV), together with mock controls. Transcriptional responses were profiled by bulk RNA sequencing using differential expression, pathway enrichment, and co-expression network analyses, integrated with placenta-enriched gene annotations from the Human Protein Atlas. Secreted cytokines were quantified using a multiplex bead assay. Results: Gestational stage strongly shaped both the transcriptional landscape and the magnitude of antiviral responses. At term, both HIV-1 and CMV induced a shared interferon-rich antiviral program, but CMV uniquely coupled this response to broad repression of mitochondrial and lipid metabolism, extracellular matrix and junctional pathways, and multiple placenta-enriched structural and immune genes. CMV exposure at term was also associated with remodeling of WNT signaling characterized by altered expression of Frizzled receptors and induction of the negative regulator RNF43 , consistent with receptor-level feedback control of the pathway. In contrast, HIV-1 at term preserved proliferative, antigen-presentation, and T-cell co-stimulation signatures. In early- to mid-gestation Hofbauer cells, viral exposure did not yield significant DEGs but showed coordinated pathway-level changes, with HIV-1 favoring interferon-associated signaling and CMV preferentially altering metabolic and remodeling pathways. Conclusion: Gestational stage establishes the immune–metabolic baseline of Hofbauer cells and strongly shapes their responses to viral exposure. At term, HIV and CMV converge on a shared interferon-driven antiviral program, but CMV uniquely couples this response to coordinated disruption of metabolic, structural, and signaling pathways in Hofbauer cells. These findings suggest that CMV drives a metabolically and structurally constrained antiviral state, providing a mechanistic framework linking CMV exposure to placental vulnerability and enhanced HIV susceptibility at the maternal–fetal interface.

Despite virologic suppression with ART, pregnant people living with HIV (PLWH) experience a disparate risk of chronic non-AIDS-related morbidities (NAMs) during pregnancy compared to people without HIV infection including preterm labor and small for gestational age. Many studies postulate that NAMs reflect immunological dysfunction from underlying continuous inflammation. Extracellular vesicles (EV) are fundamental to both HIV immune pathogenesis and maternal-placental-fetal systemic intercellular networking. Circular RNAs (CircRNA) are enriched within EVs and are readily transmissible with disease-specific functional outcomes in recipient cell populations. However, there is limited research addressing the intersection of EV circRNA and HIV during pregnancy. Small RNA (smRNA) cargo of EV-enriched fractions derived from the plasma of pregnant PLWH (n = 8) was compared to that of pregnant people living without HIV (PLWoH, n = 10) using low-input RNA sequencing (Illumina PE150). Differential circRNA profiles were used to construct circRNA-miRNA-gene regulatory maps and circRNA-protein interactions (circInteractome and miRTarbase). Gene set enrichment analysis (GSEA) using Reactome on the predicted genes from the interactome networks, provided insights into the regulatory roles of the differentially expressed circRNAs of EV-enriched fractions. Differential expression analysis identified 27 significantly upregulated circRNAs of EV-enriched fractions for pregnant PLWH as compared to pregnant PLWoH. GSEA revealed physiological pathways influential to HIV reservoir establishment, latency, replication, immune activation, immunosenescence, as well as maternal-placental-fetal immune cross talk. FUS, AGO2, and EIF4A3 were the top circRNA binding proteins and are involved in scaffolding for circRNA biogenesis, EV sorting, and miRNA sponging. High-density miRNA-binding circRNAs of EV-enriched fractions highlighted circRNA-mediated suppression of HIV inhibitory mechanisms including extensive binding of hsa-miR-326 and hsa-miR-548c-3p. While many studies have compared plasma RNA profiles for PLWH compared to PLWoH, few have conducted this analysis for EVs, and we were unable to find a study specific to the unique combination of exploring RNA cargo of EV-enriched fractions in PLWH during pregnancy. This study aims to address the knowledge gap for NAMs in pregnancy by investigating EV-based intercellular communication. The results imply that novel EV circRNA-mediated regulatory mechanisms may contribute to HIV persistence, inflammation, and immune modulation in pregnancy.

Black and African American women in the United States experience disproportionately high rates of maternal and infant mortality and morbidity, including placenta-mediated complications such as preeclampsia, preterm birth, and miscarriage. These inequities arise from the interaction of social and environmental conditions with biological pathways that become embedded over the life course, with the placenta serving as a central mediator. In this review, we examine how placental biology integrates genetic variation, epigenetic regulation, paternal contributions, immune processes, and lived social context to shape pregnancy outcomes. We synthesize evidence showing that placental dysfunction, particularly immune dysregulation driven by infectious, environmental, and psychosocial stressors, contributes to placenta-mediated complications with disproportionate impacts among African American women. We highlight how reliance on racial categories in U.S. biomedical research can obscure biological inference and argue for ancestry-informed approaches, alongside self-identified ethnicity, to disentangle inherited genetic variation from socially patterned exposures. Surveying published genome-wide association studies, we show that underrepresentation of African-ancestry populations remains a major constraint on discovery and translation in pregnancy genomic research. We further describe how placental epigenetic mechanisms link socioeconomic and environmental exposures to fetal development, placental aging, and long-term maternal–child health. Finally, we discuss how pregnancy and placental datasets remain sparse and fragmented, and consider how machine-learning approaches may improve pregnancy risk prediction when designed with equity in mind, by integrating placental multi-omics, ancestry-aware genomics, clinical data, and social determinants. Together, this review positions the placenta as a critical interface through which structural inequities shape maternal–fetal health and identifies priorities for more inclusive and equitable research and health care.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01–1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log₂ fold change of −1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC.

Elucidating how HIV and cytomegalovirus (CMV) co-infection in pregnancy disrupts immune homeostasis at the maternal–fetal interface can provide a foundation for developing intervention strategies to improve infant and maternal health. Of importance is the identification of infant immune dysregulation, especially in HIV-exposed uninfected newborns (HEU). Although vertical transmission of HIV has been substantially mitigated by antiretroviral treatment, the incidence of adverse birth outcomes remains significantly higher in these infants than in those born to mothers without HIV. We hypothesize that the immune status of mothers during pregnancy impacts upon the placenta, in turn affecting infant immunity. We explore this hypothesis by examining data from key studies and clinical cohorts, aiming to ‘join the dots’ to form a body of knowledge to catalyse development of more comprehensive studies. Our narrative represents a thought piece incorporating events around HIV and CMV during the antenatal period, the impact of maternal immunity and immune events in the placenta, and how these factors produce a ‘knock-on’ effect on infant immune ontogeny and susceptibility to poor health. We introduce the concept of vertical transmission of inflammation, where in the absence of viral transmission, the effects of a maternal inflammatory milieu could profoundly impact birth and infant outcomes via placental dysfunction. This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences’.