Emmanuel Amabebe

Background: While the human placental bacteriome has been extensively studied, information regarding the virome remains limited. Initial trigger(s) and subsequent pathogenesis of spontaneous preterm birth (PTB) remain elusive. The association between subclinical placental viral infections and spontaneous preterm birth (PTB) is poorly understood.Methods: In this study, we examined fresh placental samples from women in the UK, Bangladesh, and South Africa to elucidate the virome profiles and association with spontaneous PTB. We employed shotgun metagenomics, real-time PCR, and Gram staining, complemented by bioinformatics, to detect both viruses and bacteria in the decidua and chorionic villous tissues.Findings: We identified distinct placental viromes across the three populations, with different viral species detected in 27.8% of UK, 10.1% of Bangladeshi, and 95.8% of South African women. However, no virus was associated with preterm birth. We did not identify any known pathogenic viruses in 236 placental samples, except for one preterm placenta from the Bangladeshi cohort, where human herpesvirus 6 was detected. Most of the viruses were bacteriophages present at very low abundance and low frequencies across the three cohorts. Lambdavirus lambda was detected in 14% of UK and 11% of Bangladeshi samples but was absent in South African samples. Papiine betaherpesvirus 3 was identified in 62.5% of South African placentas. Punavirus (29.1%) and Streptococcus phages (16.67%) were also prevalent in South African samples. A variety of bacterial species, including Moraxella osloensis, Delftia lacustris, Cutibacterium acnes,Escherichia coli and Staphylococcus epidermidis, were detected in samples across the three cohorts in variable frequencies but without any notable tissue immune responses. None of the viruses or bacteria was associated with PTB, except D. lacustris, which was significantly more abundant in preterm than in term placentas in the Bangladeshi cohort.Interpretation: We conclude that the human placenta harbours a virome predominated by bacteriophages and that subclinical viral infection in spontaneous PTB is rare. However, the potential opportunistic roles of these viral species warrant further investigation to clarify virome-bacteriome interactions in adverse pregnancy outcomes.

Background: Low-dose aspirin (LDA) reduces preeclampsia (PE) risk by up to 40%, yet its molecular effects on chorion trophoblast cells (CTCs), a fetal membrane lineage at the feto-maternal interface, remain obscure. CTCs form a structural and immunoregulatory barrier whose dysfunction drives inflammation-associated membrane pathology in PE. Extracellular vesicles (EVs) released by CTCs may encode cellular stress and adaptation states, offering a molecular window into aspirin’s timing-dependent effects on PE risk modification. Methods: Human CTCs were challenged with cigarette smoke extract (CSE) to model oxidative stress-driven PE pathology. Two paradigms were tested: (1) prophylactic aspirin (4 and 40 µg/mL) before and/or flanking the CSE, and (2) therapeutic aspirin after the CSE challenge. The EVs were isolated via ultracentrifugation and size-exclusion chromatography, characterized by nanoparticle tracking and immunoblotting, and profiled by quantitative mass spectrometry. A network pathway analysis and machine learning biomarker selection defined the EV-encoded molecular states. Results: The CTC-derived EVs from the CSE-exposed cells carried a PE-like proteomic signature marked by suppressed VEGF/ECM remodeling, activated TNF-p53 apoptotic signaling, and heightened inflammation. Prophylactic low-dose aspirin shifted the EV cargo toward an EV-encoded signature consistent with preserved angiogenic potential (enrichment of VEGFA, COL1A1, and MMP14) and predicted attenuation of apoptotic and NF-κB pathway activity by an Ingenuity Pathway Analysis. High-dose aspirin produced broad transcriptional suppression without an accompanying pro-angiogenic EV signature. Therapeutic (post-injury) aspirin partially attenuated the injury-associated EV cargo but did not restore the angiogenic EV signature. An exploratory machine learning analysis of EV proteomes identified a candidate prophylactic biomarker panel anchored by HSPA8, SERPINF2, COL4A1, and PLOD1, mapped to the predicted angiogenic recovery and redox-balance pathways. These EV cargo readouts represent the predicted molecular states and require functional validation before clinical interpretation. Conclusions: The CTC-derived EV proteomic signatures capture the dose- and timing-dependent aspirin effects in this in vitro CTC model, positioning the chorion as a candidate pharmacological “secondary responder” favoring cellular resilience over classical anti-inflammatory suppression. As an exploratory hypothesis-generating study, EV-based molecular profiling could provide a foundation for future investigations aimed at stratifying aspirin responders from non-responders, although clinical validation in maternal plasma cohorts will be required before any translational application.

Around 10% of global births are preterm (before 37 weeks of gestation), posing a significant challenge to maternal and neonatal health. Preterm infants face an increased risk of mortality and long-term health complications, impacting their survival and development across all life stages. Despite decades (~ 80 years) of research, effective methods to predict and prevent idiopathic or spontaneous preterm birth remain limited. Therefore, a deeper understanding of the pathophysiology of spontaneous preterm birth is warranted. This review explores some aspects of recent progress in unravelling the complex pathophysiology of both normal and preterm human birth. We present parturition as an inflammatory event, triggered by stressors affecting the uterine reproductive tissues (myometrium, decidua, and cervix), and involving multiple endocrine and paracrine pathways. These pathways, along with signals from fetal membrane senescence and the vaginal microbiome, contribute to labor induction. Proposed perspectives in parturition research include using mathematical modeling and machine learning (artificial intelligence) to map pregnancy trajectories and identify patient phenotypes associated with preterm birth risk. Additionally, incorporating preterm birth history into routine life course medical surveillance for affected individuals and their offspring is recommended. Finally, increased investment and prioritization from national funding bodies, along with greater support for international collaborations, are essential to identify the causes of preterm birth across multiple populations and develop new, effective treatments.

Problem: We tested the hypothesis that oxidative stress (OS)‐induced inflammatory response in decidual cells (DECs) may transfer and/or trigger the release of interferon epsilon (IFNε)‐positive extracellular vesicles (EVs) from vaginal epithelial cells (VECs) to minimize vaginal disturbances.Method of Study: VECs were treated for 48 h under the following conditions: (1) standard VEC media, (2) OS‐inducing cigarette smoke extract (CSE); and supernatant from (3) normal/untreated DECs, and (4) CSE‐treated DECs. The concentration of cytoplasmic, secreted, and VEC‐derived EV bound IFNε (n = 3 each) was measured by enzyme‐linked immunosorbent assay (ELISA). EVs were isolated from culture media by cushioned‐density gradient ultracentrifugation and characterized by immunoblotting and nanoparticle tracking analysis.Results: Induction of OS in VECs with CSE increased intracellular IFNε in VECs (p = 0.0007) but not free or EV‐bound IFNε compared to control VECs. Exposure to conditioned media from untreated and CSE‐treated DECs induced increased intracellular (p = 0.004, p = 0.049) and free IFNε (p = 0.04, p = 0.03) from VECs. VEC‐derived EVs (126 ± 11.8 nm) expressed exosome markers, and did not change in size regardless of the treatment but decreased in number due to exposure to untreated (p = 0.004) and CSE‐treated DECs (p = 0.025) conditioned media. Furthermore, VEC exosomal IFNε increased by 2.6‐fold (p = 0.0001, untreated DECs) and ∼4‐fold (p = 0.041, CSE‐treated DECs) compared to controls.Conclusions: Mucosal immune defense mediated by IFNε may be an innate response by VECs under OS. This was further evidenced by an overall increase in IFNε due to both physiologic and pathologic impact of decidua on VECs. IFNε may indicate a stress response by VECs or paracrine crosstalk between gestational tissues.

Bacterial vaginosis (BV) is the most commonly diagnosed vaginal infection in women of reproductive age, with most patients unaware that they have BV due to its asymptomatic nature. BV is a dysbiotic condition defined by a deviation from the healthy Lactobacillus dominance to a polymicrobial anaerobic bacterial community that increases the risk of sexually transmitted infections and adverse reproductive outcomes, including spontaneous preterm birth. The increasing number of infectious agents in BV, biofilm persistence and antibiotic resistance in the vaginal canal hinder effective treatments with antibiotics leading to consistent recurrence of BV in many women (30–70%). Like in the gut, these vaginal drug-microbiome interactions termed pharmacomicrobiomics could alter drug disposition, mechanism of action, and toxicity that reduce the efficacy of antibiotics and increase the risk of persistent and recurrent BV and its sequelae. For instance, both vaginal epithelial and bacterial cells co-exist and possess enzymes that metabolize antibiotics, and transporter proteins that expel drugs and toxins, rendering them ineffective. Despite significant progress on pharmacomicrobiomics in the gut, little is known about this phenomenon in the vaginal microenvironment, which harbors a consequential microbiota and a major source of infection and antibiotic resistance. Therefore, to improve therapeutic outcomes and reduce the rate of persistent/recurrent BV and infection-associated preterm birth, we present an overview of the evidence pertaining to the effect of vaginal microbiome-drug interactions and efficacy of antibiotics against recurrent BV. We also highlight plausible mechanistic underpinnings of these interactions and implications for treatment modalities to combat infection-associated preterm birth.

Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI) in the United States. Ascending C. trachomatis can cause pelvic inflammatory disease (PID), potentially leading to subsequent infertility, ectopic pregnancy, and adverse pregnancy outcomes. There is growing evidence implicating infections (e.g., COVID‐19, cytomegalovirus) in preeclampsia etiology, a maternal hypertensive disorder and leading cause of maternal morbidity and mortality. However, few studies have investigated the impact of STIs on preeclampsia risk. In this review, we provide an overview of the potential association between C. trachomatis and preeclampsia and identify future research needs through a critical evaluation of epidemiologic, in vitro, and in vivo studies. Unfortunately, current methodological limitations such as lower‐quality study designs, selection bias, confounding bias, and variations in chlamydia diagnostic methods inhibit our understanding of the impact of C. trachomatis on preeclampsia. In addition, bench‐side approaches such as animal models and in vitro studies have not elucidated the mechanisms linking C. trachomatis to preeclampsia. Understanding the biological pathways that could be disrupted by chlamydia is important as it may ultimately guide the development and use of novel therapeutics to augment standard antibiotic therapy to reduce pathology.

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer’s disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively.

Limited studies have investigated the role of the microbiota in hypertensive disorders of pregnancy (HDP), particularly preeclampsia, which often results in preterm birth. We evaluated 23 studies that explored the relationship between gut, vaginal, oral, or placental microbiotas and HDP. Scopus, ProQuest Health Research Premium Collection, ProQuest Nursing & Allied Health Database, EBSCO, and Ovid were searched for relevant literature. Majority (18) of studies focused on the gut microbiota, and far fewer examined the oral cavity (3), vagina (3), and placenta (1). One study examined the gut, oral, and vaginal microbiotas. The consensus highlights a potential role for microbiota dysbiosis in preeclampsia and HDP. Especially in the third trimester, preeclampsia is associated with gut dysbiosis—deficient in beneficial species of Akkermansia, Bifidobacterium, and Coprococcus but enriched with pathogenic Campylobacterota and Candidatus Saccharibacteria, with low community α‐diversity. Similarly, the preeclamptic vaginal and oral microbiotas are enriched with bacterial vaginosis and periodontal disease‐associated species, respectively. The trend is also observed in the placenta, which is colonized by gastrointestinal, respiratory tract, and periodontitis‐related pathogens. Consequently, a chronic proinflammatory state that adversely impacts placentation is implicated. These observations however require more mechanistic studies to establish the timing of the preceding immune dysfunction and any causality.

Obesity is a global epidemic with alarmingly high prevalence rates worldwide. The increasing incidence of obesity among reproductive age women, which progresses to obesity in pregnancy is of particular concern. A successful pregnancy is dependent on the balanced interaction between maternal cardiometabolic function, genetic predisposition, and optimal placental development. Maternal obesity, both pre-pregnancy and gestational, has been associated with adverse outcomes including poor fetal development, stillbirth, preterm birth, and metabolic complications later in life. To gain a more comprehensive understanding of the mechanistic interplay of key mediators of obesity-associated placental dysfunction and adverse pregnancy outcomes, we conducted a review of 24 studies that investigated placental dysfunction and maternal obesity retrieved from MEDLINE, LILACS and EMBASE. The findings demonstrate that maternal obesity is a well-established risk factor for poor placental function. Pre-pregnancy obesity alters the placental transcriptome. Maternal obesity during gestation induces changes in placental morphology, dysregulated placental metabolism, inflammation and oxidative state, as well as endothelial dysfunction. There is also clear evidence that maternal obesity is associated with altered placental angiogenesis/vascularisation which increases the risk of early-onset preeclampsia. Studies show a link between maternal obesity and increased placental vascular disorders, placental weight, placental volume and birth weight. These obesity-related placental disorders are often associated with insulin resistance and gestational diabetes mellitus.

Sickle cell disease (SCD) poses an increased risk of infertility, pregnancy complications and maternal and perinatal mortality among women of reproductive age. This risk is particularly higher for women in sub-Saharan Africa, where the disease burden is highest and access to comprehensive health care is limited, as well as in other countries with a high SCD prevalence due to migration. Disease-modifying treatments for SCD could directly and indirectly harm the ovaries, potentially compromising the quality and quantity of existing oocytes. Therefore, it is essential to explore alternative interventions, such as nutritional modifications that are less harmful and cost-effective in order to improve reproductive outcomes and enhance the overall well-being of both mother and child in this population. Maintaining optimal levels of B12 may possibly provide benefits to the ovaries and pregnancy by decreasing homocysteine levels, increasing nitric oxide (NO) bioavailability and promoting antioxidant and anti-inflammatory activities. Individuals living with SCD are more susceptible to vitamin B12 (B12) deficiency. However, there is a lack of clinical data investigating the relationship between systemic levels of B12, its supplementation, and reproductive outcome measures in SCD women. Therefore, this review aims to examine the current evidence regarding the impact of SCD on female reproductive health and the role of B12 in the reproductive biology of women living with SCD. Lay summary: Poor reproductive health is a concern for patients with sickle cell disease (SCD). SCD can lead to damage to the ovaries. Most of the therapies for sickle cell disease are toxic to the ovaries, expensive and unavailable to affected women, particularly those living in resource-poor areas such as sub-Saharan Africa. There is a need to seek less harmful and affordable interventions such as nutrition to improve reproductive outcomes for women with SCD who are of child-bearing age. Good levels of vitamin B12 have been found to maintain ovarian health and pregnancy. Patients with SCD have been reported to have a high risk of vitamin B12 deficiency, but the impact of B12 on reproduction in this group of women is yet to be evaluated. The review explores current evidence of the impact of both SCD and B12 on female reproduction.