Introduction Fetal growth restriction (FGR) is thought to originate from placental insufficiency, but late-onset FGR fetuses often lack signs of impaired uteroplacental circulation in Doppler sonography and distinction from small for gestational age (SGA) is challenging. SGA fetuses are often mistaken for constitutionally small and healthy. We aimed to investigate placental pathology in late-onset FGR and SGA compared to controls and to validate a novel semiquantitative scoring system for its clinical utility. Methods In this prospective cohort study of singleton pregnancies ≥32 weeks, placentas from late-onset SGA were examined in comparison to controls. The SGA cohort was subdivided into FGR (birthweight < 3rd percentile and/or pathological Doppler) and SGA 3rd-10th percentile (remaining cases with normal Doppler). Placental pathology was assessed based on the Amsterdam Criteria. Results A total of 41 placentas were evaluated (13 FGR, 10 SGA 3rd-10th and 18 controls). FGR placentas showed higher cumulative scores and more frequently morphological signs of placental insufficiency, while SGA 3rd-10th and controls mostly showed lesions with compensatory changes. Maternal vascular malperfusion (MVM) lesions were observed in 100% of FGR, 80% of SGA 3rd-10th and 27.8% of control placentas. Conclusion This study reveals a high prevalence of placental lesions, particularly MVM, in late-onset FGR pregnancies, but also in late-onset SGA without Doppler abnormalities. The novel scoring system shows promise as a practical tool for reproducible placental evaluation and may improve postnatal identification of clinically significant placental insufficiency. These findings underline the importance of routine placental examination and the need for further standardization of diagnostic criteria.

The human endometrial immune landscape is critical for homeostasis and pregnancy success, yet its dynamic remodeling across the menstrual cycle and in pathology remains poorly characterized. Here, we construct a comprehensive immune cell atlas of the human endometrium, profiling 53 healthy women and 34 chronic endometritis (CE) patients across precisely staged menstrual cycle phases. Our analysis reveals NK and T cells as dominant constituents, with NK cells increasing while T cells decreasing progressively from proliferative to secretory phase. B cells, mast cells, and innate lymphoid cells remain consistently low. Of the two tissue-resident NK subsets, CD11c⁺ NK cells accumulate during the secretory phase and early pregnancy. CE disrupts this landscape, marked by CD11c⁺ NK cell reduction, local B cell proliferation and differentiation, and formation of ectopic lymphoid aggregates comprising germinal-center-B-like cells and T follicular helper-like cells. Using a murine CE model and a subsequent multi-center cohort study we demonstrate that these aggregates compromise pregnancy outcomes in a Tfh-like-cell-dependent manner. Collectively, we establish a detailed immune cell atlas of the cycling human endometrium and define a pathogenic mechanism for adverse pregnancy outcomes. The immune landscape of human endometrium is remodeled across the menstrual cycle. The authors here provide a comprehensive immune atlas of these changes, and show that ectopic lymphoid aggregates, composed of germinal-center-B-like cells and T follicular helper-like cells, form in mouse and human chronic endometritis, which might lead to adverse pregnancy outcomes.

Structural and functional integrity of the blood-brain barrier (BBB) is crucial for maintaining brain homeostasis. Preeclampsia, characterized by new-onset hypertension and endothelial dysfunction in pregnancy, often involves BBB disruption and neurological complications. Small extracellular vesicles (sEVs) have emerged as potential drivers of BBB disruption during preeclampsia; however, their impact on maternal brain health, particularly at the cellular level, remains understudied. Here, the effect of preeclampsia-derived sEVs on BBB integrity and cellular responses of brain endothelial cells, microglia and astrocytes was investigated. Circulating sEVs were isolated from plasma of healthy women and women with late-onset preeclampsia and studied in human-based mono-, bi- or tri-culture models using transwell and microfluidic (BBB-on-a-chip) systems. In these models, EV-associated signals were detected within brain endothelial cells consistent with intracellular uptake and trafficking. EV-derived cargo was detected in cells on the abluminal side of the endothelial layer, suggesting possible transfer across the barrier, although the underlying mechanism remains unclear. Exposure to preeclampsia-derived sEVs (PE-sEVs) was also associated with changes in brain endothelial cell protein composition and subcellular localization, accompanied by functional alterations of BBB properties, including increased permeability. Finally, astrocytes and microglia responded to PE-sEV exposure, as evidenced by increased IBA1 and GFAP expression, IL-6 release, and enhanced astrocyte migration. These findings suggest that circulating sEVs, including those of placental origin, may be involved in maternal brain alterations in preeclampsia potentially through effects on BBB integrity and glial activation. This may indicate the possible relevance of circulating sEVs as biomarkers and in the pathophysiology of the disease. KEY POINTS: Preeclampsia is a pregnancy-related condition involving high blood pressure and endothelial dysfunction, and is often associated with disruption of the blood-brain barrier (BBB) and neurological complications. Circulating small extracellular vesicles (sEVs) normally increase during pregnancy but are further elevated in preeclampsia, and may carry inflammatory cargo to the maternal brain. Using in vitro models, including an organ-on-a-chip, composed of human brain endothelial cells, microglia and astrocytes, this study examined how sEVs from healthy and preeclamptic pregnancies affect BBB properties, and glial activation. Results support the notion that preeclampsia-derived sEVs increase BBB permeability, traverse the endothelial layer, and induce glial responses including microglial activation and astrocyte reactivity by increased IL-6 release and cellular motility. The observed alterations may link placental dysfunction to maternal cerebrovascular injury, highlighting sEVs as potential modulators of brain damage in preeclampsia and as promising diagnostic or therapeutic targets.

INTRODUCTION:Maternal blood composition undergoes profound changes during pregnancy to meet immunological, hemostatic, and oxygen demands. Despite the importance of these adaptations, the mechanisms regulating maternal hematopoiesis remain poorly understood. An interaction between maternal hematopoietic stem cells (HSCs) and placenta-derived extracellular vesicles (EVs) may play a key role in this process. METHODS:Primary human bone marrow-derived CD34+ HSCs were cultured for seven days in the presence of placenta-derived EVs. EVs were isolated from 3-h ex vivo human placenta perfusions followed by serial ultracentrifugations. EV quality and integrity were assessed by Western blotting for characteristic markers, nanoparticle tracking analysis for size distribution, and transmission electron microscopy. HSC capture of fluorescence-labelled EVs was confirmed by flow cytometry. HSC differentiation was monitored by flow cytometric analysis of lineage-specific surface markers. RESULTS:Specific EV subpopulations were successfully enriched. During the 4-h culture period, hematopoietic stem cells (HSCs) internalized significantly more small extracellular vesicles (sEVs) than large extracellular vesicles (lEVs). After 7 days of incubation, both sEVs and lEVs promoted enhanced differentiation of HSCs into CD235a+ erythroid cells and CD14+ monocytes compared with untreated controls. CONCLUSION:The findings indicate that fetal EVs released into the maternal circulation can modulate maternal hematopoiesis, particularly enhancing erythropoiesis and monocytopoiesis.

Human reproduction involves a series of highly regulated biological processes, including oogenesis, fertilization, embryo implantation, and maternal-fetal interactions. Disruptions in these processes often result in reproductive disorders, including infertility, recurrent pregnancy loss, preeclampsia, and preterm birth. Currently available therapeutic strategies are often limited by potential harm to gametes, embryos, or fetuses and off-target effects. Engineered extracellular vesicles (EVs) have emerged as a promising approach due to their excellent biocompatibility, stability in circulation, prolonged circulation time, efficient cargo delivery, and potential for cell- or tissue-specific targeting. While still in the preclinical stage, engineered EVs are already reshaping basic research by enabling cell-specific modulation of reproductive and immune processes. By exploring engineering techniques, novel biomarkers, and new targeting approaches in animal models and clinical trials, we provide new insights into how engineered EVs could transform the treatment of female reproductive disorders. We also discuss ongoing challenges, including issues of manufacturing scalability, regulatory approval, and translating preclinical efficacy into clinical settings. With further collaboration between researchers, clinicians, and biotech innovators, engineered EVs could one day become a powerful tool to support women's reproductive health.