RARE DISEASE
Placental insufficiency
Placental insufficiency
Placental insufficiency
Synonyms: Uteroplacental vascular insufficiency
Synonyms: Uteroplacental vascular insufficiency
Synonyms: Uteroplacental vascular insufficiency
Drug discovery
1
drug
With orphan designation
Overview
Placental insufficiency is a progressive deterioration in placental function, impairing oxygen/nutrient transfer to the fetus, often linked to preeclampsia, intrauterine growth restriction (IUGR), and preterm birth [1][3][13]. It is a leading contributor to perinatal morbidity and mortality, with complications including stillbirth, hypoxic-ischemic encephalopathy, and long-term neurodevelopmental/cardiometabolic risks [1][9][17]. Diagnosis relies on Doppler ultrasonography, fetal biometry, and clinical monitoring [6][9].
Categories: rare gynecological and obstetric diseases
Research Papers
1,029 drug discovery papers about Placental insufficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,029 drug discovery papers about Placental insufficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Maternal Cardiovascular Phenotype in Fetal Growth Restriction with or Without Pre-Eclampsia: Insights from Echocardiography and Clinical Implications.
Fetal growth restriction (FGR) has traditionally been attributed to placental insufficiency. However, accumulating evidence suggests that maternal cardiovascular maladaptation contributes to disease expression, clinical heterogeneity, and long-term maternal cardiovascular risk. To review maternal echocardiographic findings in pregnancies complicated by FGR, with or without preeclampsia and to explore the role of cardiovascular phenotyping in risk stratification and clinical management. Narrative review of the current literature, including observational studies, systematic reviews, meta-analyses, and expert consensus statements on maternal hemodynamics and echocardiographic assessment in FGR. FGR is associated with a maladaptive cardiovascular profile characterized by reduced cardiac output, increased systemic vascular resistance and adverse cardiac remodeling. Echocardiography frequently identifies subclinical myocardial dysfunction, including impaired diastolic function and reduced global longitudinal strain despite preserved ejection fraction. Distinct maternal cardiovascular phenotypes emerge across the FGR spectrum, ranging from high-risk hypodynamic, resistance-dominant phenotypes to intermediate and low-risk phenotypes with preserved hemodynamic adaptation. Integration of maternal cardiovascular assessment with fetal Doppler findings may improve risk stratification and support phenotype-guided surveillance and therapeutic decision-making. Persistent postpartum cardiovascular abnormalities further support the concept of pregnancy as a cardiovascular stress test and identify women at increased long-term cardiovascular risk. FGR should be viewed as the clinical manifestation of a complex maternal-placental-cardiovascular interaction rather than an isolated placental disorder. Maternal cardiovascular phenotyping has the potential to refine risk stratification, support hemodynamic-guided management, and identify women who may benefit from structured long-term cardiovascular surveillance.
2026-07-11 | Complement as a driver of immune-vascular heterogeneity across preeclampsia subtypes: toward a precision medicine framework.
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, traditionally defined as a hypertensive disorder of pregnancy but increasingly recognized as a heterogeneous syndrome with diverse biological origins. Emerging evidence indicates that distinct pathogenic pathways-including placental insufficiency, maternal cardiometabolic dysfunction, and intrinsic immune dysregulation-contribute to different clinical phenotypes of the disease. Among these, the complement system has gained attention as a central regulator of immune-vascular interactions during pregnancy. Recent studies demonstrate that tightly controlled complement activation is required for normal placental development, whereas dysregulation of this system contributes to endothelial injury, inflammation, and microvascular dysfunction characteristic of PE. Importantly, complement activation patterns differ across disease subtypes: classical pathway activation predominates in placental-driven early-onset PE, chronic low-grade alternative pathway activation is associated with maternal metabolic disease, and genetic or functional defects in complement regulation define a subset of severe, complement-mediated cases with overlap features of thrombotic microangiopathy. Despite these advances, current diagnostic and therapeutic approaches remain largely non-specific and fail to account for this biological heterogeneity. Here, we propose a subtype-based framework of PE centered on complement dysregulation, integrating mechanistic, genetic, and clinical evidence. This model links distinct complement activation patterns to disease trajectories and identifies corresponding biomarker signatures and therapeutic targets. By redefining PE as a spectrum of complement-stratified disorders, this Review provides a conceptual foundation for precision diagnostics and mechanism-guided therapy. Such an approach has the potential to improve risk stratification, enable earlier detection, and support the development of targeted interventions tailored to individual disease mechanisms.
2026-06-29 | Vaginal microbiota in the first trimester of pregnancy and the development of placental insufficiency
Fetal growth restriction and preeclampsia, the underlying pathogenesis of which is placental insufficiency, are among the leading causes of perinatal and maternal morbidity and mortality worldwide. Objective. To study the association between vaginal microbiome and placental protein levels in the first trimester of pregnancy with the risk of developing of placental insufficiency. Material and methods. The study included 283 patients without history of obstetrical, gynecologic, or medical conditions. Each patient had their placental protein levels assessed-human chorionic gonadotropin (hCG) and placental-associated plasma protein A (PAPP-A) — based on the initial screening, and their vaginal microbiota in the first trimester of pregnancy was analyzed using polymerase chain reaction. Depending on whether placental insufficiency subsequently developed, all patients were divided into two groups: Group 1 — 203 patients without placental insufficiency; Group 2 — 80 patients whose pregnancy was complicated by the development of placental insufficiency. Results. Patients of Group 2 had statistically significant lower concentrations of placental proteins — hCG and PAPP-A — as well as higher levels of Gardnerella vaginalis, Prevotella bivia, Porphyromonas spp., and Eubacterium spp. — were detected in the first trimester of pregnancy compared to those in Group 1. According to the study results, with a PAPP-A MoM level ≤0.486 based on the first prenatal screening data and the number of Sneathia spp., Leptotrichia spp., and Fusobacterium spp. bacteria, A vaginal microbiota with ≤107.3 DNA copies is associated with a high risk of developing placental insufficiency. Conclusion. Patients with reduced levels of placental proteins based on the initial prenatal screening and higher numbers of opportunistic microorganisms in the first trimester of pregnancy have a higher risk of developing placental insufficiency in late gestation. Timely correction of the vaginal microbiota during the preconception period and early pregnancy may be an important way to prevent placental insufficiency.
2026-06-25 | USP22 suppresses trophoblast cell necroptosis in preeclampsia by stabilizing KAT2A-mediated histone acetylation at the SFRP1 promoter.
Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis. Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE. USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo. USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.
2026-06-01 | A perinatal approach for unraveling mitochondrial function in preeclampsia and fetal growth restriction: a role for mitochondrial-targeted therapies.
Preeclampsia (PE) is a complex hypertensive disorder resulting from placental insufficiency during pregnancy. PE contributes to maternal and fetal morbidity and mortality and often co-occurs with fetal growth restriction (FGR); these two are both considered placental insufficiency syndromes. Alterations in mitochondrial function levels due to placental insufficiency play an important role in the pathophysiology of PE and FGR. Changes in these processes can lead to maternal and fetal organ damage with subsequent risk to develop cardiovascular disease. This review therefore investigates the effects of placental insufficiency syndromes, including PE and FGR, on mitochondrial function and its underlying mechanisms, using a perinatal approach including maternal heart and kidney, placenta, and fetal heart and kidney. This review also explores the potential of mitochondrial-targeted therapies in mitigating these effects. We provide an overview of the literature at hand and demonstrate the critical role of mitochondrial function in different organ systems. Subsequently, we also discuss the need for mitochondrial-targeted therapies, in particular, focused on oxidative stress, metabolic pathways, mitochondrial quality control, and mitochondrial calcium handling. This knowledge provides guidance for future studies and potential therapies to improve PE and FGR and their consequences for maternal and fetal outcomes during pregnancy and cardiovascular health later in life.
proteins
2026-05-27 | The Contribution of Ultrasound and Doppler Studies on Impaired Intrauterine Conditions and the Development of Future Disease.
The Barker hypothesis links intrauterine conditions, mainly low birth weight, subject to poor nutrition with paradoxically improved standards of living and nutrition after World War II in Western countries, to adult disease, mainly coronary heart disease. The limitations of his hypothesis include the fact that it is based only on human epidemiological data and animal studies, and also that it is difficult to isolate the effect of the intrauterine environment from postnatal conditions, familial and genetic background. In the last 20 years, the introduction of ultrasound and Doppler techniques in the assessment of fetal and maternal vascularity added a major contribution to the evaluation of the intrauterine environment. Studies based on ultrasound and Doppler assist in differentiating between prematurity and fetal growth restriction (FGR), mainly in those with placental insufficiency, and postnatal morbidity and even mortality. In addition, the Pedersen hypothesis regarding fetuses with overgrowth, mainly with diabetic mothers, states that they are also prone to postnatal morbidity. However, most of the studies on the issue do not emphasize the effects of the intrauterine environment on fetal organs, such as the brain, heart, liver, kidneys and pancreas in FGR and fetal overgrowth, that may impose a different prognosis in later life. This narrative review aims to summarize current evidence from animal and human studies regarding the impact of intrauterine undernutrition and overnutrition on fetal organ development, and to evaluate how ultrasound and Doppler findings may contribute to understanding the link between the intrauterine environment and postnatal morbidity.
2026-05-19 | PATHOMORPHOLOGICAL AND IMMUNOHISTOCHEMICAL FEATURES OF CHRONIC PLACENTAL INSUFFICIENCY IN CONGENITAL INFECTIONS UNDER THE CONDITIONS OF KARAKALPAKSTAN
Chronic placental insufficiency (CPI) remains a critical obstetric complication, serving as a primary vector for intrauterine growth restriction, preterm birth, and perinatal mortality. In regions experiencing severe ecological degradation, such as the Republic of Karakalpakstan in the Aral Sea disaster zone, the etiology of CPI is profoundly compounded by environmental toxicity, high regional rates of maternal anemia, and the prevalent transmission of congenital (TORCH) infections. This comprehensive report investigates the synergistic impact of environmental factors and infectious agents on the pathomorphological and immunohistochemical (IHC) architecture of the human placenta. Utilizing advanced digital histomorphometry and computational image analysis, the study quantifies key biomarkers associated with angiogenesis (VEGF), cellular proliferation (Ki-67), apoptosis (Caspase-3), and localized inflammatory responses (CD68).
2026-04-29 | Placental hormones, IGF-1, and early-life growth: endocrine links between birth size and infant metabolic programming-a systematic review.
The purpose of this study is to systematically review human evidence linking placental hormones and IGF-1 with fetal growth, birth size, and early-life metabolic programming, and to identify disease-specific translational signals relevant to fetal growth restriction, metabolically complicated pregnancy, and extreme prematurity. A systematic review of PubMed and Scopus was performed for human studies published from January 2000 to March 2025. Eligible studies examined placental growth hormone, human placental lactogen, placental IGF-axis markers, or related stress-hormone pathways in relation to birth size, fetal or infant growth, or early metabolic outcomes. Reporting was aligned with PRISMA 2020. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I principles for observational studies. Because of substantial clinical and methodological heterogeneity, findings were synthesized narratively. Thirty-seven included studies showed that mid-gestation placental growth hormone had the most consistent positive associations with fetal growth and birth size, whereas early placental growth hormone was less informative. Cord blood IGF-1 was the most reproducible endocrine correlate of birth length and weight. Reduced maternal or placental lactogen signals and lower placental 11β-HSD2 activity clustered with placental insufficiency and fetal growth restriction, while diabetic pregnancies showed a shift toward adiposity-related outcomes. In extreme prematurity, abrupt loss of placental endocrine support created a translational window in which rhIGF-1/rhIGFBP-3 replacement emerged as the clearest mechanism-based intervention, although current clinical evidence remains preliminary. Placental endocrine markers should not be used as standalone screening tools. Their main value at present is mechanistic and translational: combined hormone patterns may refine biological understanding and risk stratification within defined maternal and neonatal disease frameworks, while IGF-1 replacement in extreme prematurity represents the most credible current therapeutic lead. • Placental hormones and IGF-1 are linked with fetal growth, birth size, and neonatal metabolic adaptation, but 45 published evidence is heterogeneous and clinically fragmented. • This systematic review organizes the human data within fetal growth restriction, diabetic/LGA pregnancy, and extreme prematurity frameworks and identifies translational signals-especially early IGF-1 replacement in extreme prematurity-rather than standalone diagnostic biomarkers.
2026-03-28 | The Impact of Fetal Growth Restriction on Myocardial Development from Fetal Life to Early Childhood: A Narrative Review.
Background/Objectives: Fetal growth restriction (FGR), historically termed intrauterine growth restriction (IUGR), is a multifactorial condition in which the fetus fails to reach its genetically determined growth potential, most often due to placental insufficiency. Beyond its link with increased perinatal morbidity and mortality, FGR has been associated with long-term cardiovascular risk through early-life programming. The developing fetal heart is vulnerable to chronic hypoxia and nutrient deprivation, potentially inducing structural and functional alterations with lifelong consequences. This narrative review summarizes and critically appraises experimental and clinical evidence on the impact of FGR on myocardial development and cardiovascular health from fetal life to adulthood. Methods: We conducted a narrative review using a structured literature search of studies published in the last 15 years in PubMed and Scopus, focusing on experimental, imaging, and epidemiological research evaluating cardiac structure, function, and long-term cardiovascular outcomes in FGR. Evidence from fetal and neonatal echocardiography, including Doppler and speckle-tracking techniques, as well as molecular and histological studies, was examined. No statistical meta-analysis was performed. Results: FGR has been associated with reduced cardiomyocyte number, altered myocardial architecture, increased interstitial fibrosis, and persistent ventricular remodeling. Functional studies suggest early impairments in systolic and diastolic performance, with alterations in cardiac energy metabolism and epigenetic regulation. Advanced imaging may enable detection of subclinical cardiac dysfunction in utero and early postnatally. Epidemiological data suggest an increased risk of hypertension, ischemic heart disease, heart failure, and metabolic disorders in adulthood among individuals born growth-restricted. Conclusions: FGR represents an early cardiovascular risk condition. Improved understanding of fetal cardiac programming may help refine risk stratification, surveillance, and preventive strategies to reduce long-term cardiovascular morbidity in individuals born growth-restricted.
2026-03-11 | Insights from animal models: Dissecting the independent roles of oxygen and nutrients in the fetal origins of cardiovascular disease.
Depending on the pregnancy complication, substrate delivery to a developing fetus can be reduced, changing the course of fetal growth below the genetically determined in utero growth potential, resulting in fetal growth restriction (FGR). FGR is linked to an increased risk of developing cardiovascular disease (CVD) in later life. When caused by placental insufficiency, FGR is characterized by fetal hypoxaemia and hypoglycaemia due to reduced substrate supply to the fetus. However, other common pregnancy complications exist, where fetal hypoxaemia or hypoglycaemia may or may not occur. It is therefore necessary to understand the independent and synergistic contributions of hypoxaemia and hypoglycaemia to the fetal origins of CVD. In doing so, this knowledge will aid in the development of intervention strategies. The aim of this review is to provide mechanistic insights by comparing findings across different paradigms of developmental programming using animal models of FGR, with consideration of the timing, duration, and severity of the insult, and the ventricles and fetal sex studied.
antibodies
2026-03-12 | Predicting chronic placental insufficiency in patients with a complicated obstetric history at pregnancy planning stage
Introduction. Chronic placental insufficiency (CPI) is one of the leading causes of fetal growth restriction (FGR), perinatal loss, and complicated pregnancy. Currently, no validated methods for predicting CPI during pregnancy planning are available, which complicates high-risk patient stratification early and enabling timely prevention. Aim: to develop a mathematical model for predicting CPI risk in women with a complicated obstetric history at the pre-pregnancy preparation stage. Materials and Methods . A retrospective clinical study assessing 462 patients with a complicated obstetric history was conducted. The outcomes of previous pregnancies, concomitant extragenital diseases, circulation of criterial (anti-β2glycoprotein and anti-cardiolipin antibodies, lupus anticoagulant) and non-criterial (anti-annexin 5, anti-phosphatidylserine, anti-phosphatidylinositol, anti-prothrombin, anti-human chorionic gonadotropin) antiphospholipid antibodies (APA), indicators of lymphocyte subpopulation composition, coagulation profile, and genetic thrombophilia were evaluated. Enzyme-linked immunosorbent assay, flow cytometry, ultrasound, and histological diagnostics were used. Binary logistic regression was applied to construct a prognostic model, and the diagnostic significance of the indicators was assessed using ROC curves. Results. Detected APA high titers and/or lupus anticoagulant were associated with significantly elevated CPI incidence (63.1% vs. 4.6%; p < 0.001) and FGR (43.4% vs. 4.6%; p < 0.001). Immunological imbalance (increased percentage of B-lymphocytes and NK cells) increased CPI risk by 1.3–5.5 times. The constructed prediction model, which included indicators of immunological activity and comorbidity, demonstrated high accuracy: AUC = 0.89, sensitivity 85.7%, specificity 85.7%. Conclusion. The developed mathematical model allows for highly accurate prediction of CPI risk developing in women with a complicated obstetric history even before pregnancy, which opens up avenues for personalized selection of preventive measures, including immunomodulatory therapy and dynamic monitoring, and contributes to lowering frequency of perinatal complications.
2025-12-12 | Immune-mediated mechanisms and maternal-fetal interface dysfunction in obstetric antiphospholipid syndrome.
Obstetric antiphospholipid syndrome (OAPS) is a complex autoimmune disorder that significantly compromises pregnancy, manifesting as recurrent miscarriage, stillbirth, placental insufficiency, and preeclampsia. Its increasing prevalence underscores the pressing need to elucidate its multifaceted pathogenic mechanisms to improve maternal and fetal outcomes. While traditionally attributed to thrombosis driven by antiphospholipid antibodies (aPL), emerging evidence indicates that OAPS can disrupt placental perfusion, impair trophoblast proliferation and invasion, and compromise placental angiogenesis even in the absence of overt thrombotic events. Beyond direct effects on trophoblasts and vascular remodeling, aPLs profoundly perturb the immune milieu at the maternal-fetal interface, encompassing complement activation, excessive formation of neutrophil extracellular traps (NETs), dysfunction of decidual natural killer cells and macrophages, and dysregulated B cell responses. These immune-mediated alterations collectively establish a sustained pro-inflammatory environment that undermines placental development and predisposes to adverse pregnancy outcomes. This review provides a comprehensive synthesis of the immunopathogenic mechanisms of OAPS that extend beyond thrombosis, and emphasizes the intricate crosstalk between immune cells and the complement-NET axis. A deeper understanding of these immune-mediated pathways may inform the development of targeted therapeutic strategies to optimize maternal and fetal outcomes in affected pregnancies.
2025-06-30 | Chronic Histiocytic Intervillositis: Insights into Immunopathogenesis and Prospective Treatments
Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory disorder associated with adverse pregnancy outcomes, including fetal growth restriction, miscarriage, and stillbirth. Its diagnosis is made retrospectively via histopathology, limiting timely intervention. This review explores the emerging hypothesis that CHI is an alloimmune condition resulting from aberrant maternal immune responses to paternally derived fetal antigens. Key findings from current literature include perivillous fibrin deposition and maternal histiocyte accumulation in the placental intervillous space, both of which disrupt maternal–fetal exchange. Additional evidence points to complement activation, particularly C4d and C5b-9 deposition, increased CD8+ T cell infiltration, and inflammasome pathway involvement, all contributing to placental insufficiency. The role of anti-HLA antibodies remains under investigation, with conflicting data on their presence and clinical significance. However, abnormal HLA class II expression on the syncytiotrophoblast in CHI may facilitate maternal alloimmune recognition and antibody production. Current treatments, including anticoagulants and immunosuppressants, show limited efficacy, and no standardised management exists. The findings underscore a critical need for prospective studies, biomarker discovery, and targeted immunomodulatory therapies. Improved understanding of CHI pathogenesis may facilitate earlier diagnosis, personalised treatment, and prevention of recurrence and primary disease in future pregnancies.
2025-06-08 | Certolizumab pegol to prevent adverse pregnancy outcomes in patients with antiphospholipid syndrome and lupus anticoagulant (IMPACT): results of a prospective, single-arm, open-label, phase 2 trial.
The aim of this study was to evaluate whether certolizumab pegol, a tumour necrosis factor α inhibitor with little or no transport across the placenta, added to standard treatment with low molecular weight heparin plus low dose aspirin, reduces rates of adverse pregnancy outcome (APO) in high-risk pregnancies with antiphospholipid syndrome (APS). We assessed treatment with certolizumab in pregnant patients with APS and lupus anticoagulant, administered gestational weeks 8 through 28, in addition to standard treatment. The primary APO was a composite of fetal death ≥10 weeks' gestation or pre-eclampsia with severe features or placental insufficiency requiring delivery <34 weeks' gestation. Target sample size was 45 with expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively observed population of similarly managed APS pregnancies. Fifty-one patients were enrolled, and 9 had primary APO (17.6%; 95% CI, 8.4%-30.9%). Excluding 6 patients who had a pregnancy loss <10 weeks' gestation or fetal loss due to genetic abnormalities, primary APO occurred in 9 of the 45 patients (20%; 95% CI, 9.6%-34.6%), meeting predetermined criteria for efficacy of certolizumab and significantly lower than rates in historical controls. Median gestational age at delivery in certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of pre-eclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections and no new cases or severe flares of lupus. Certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.
2024-09-12 | Assessing the effectiveness of preventing placenta-associated complications in patients with burdened obstetric history and circulating antiphospholipid antibodies
Introduction . The role of antiphospholipid antibody (APA) carriage in the pathogenesis of pregnancy failure is one of the most recently debated issues. To date, no unified therapeutic approach to immunotherapy of antiphospholipid syndrome (APS) in pregnancy exists. Intravenous immunoglobulins (IVIG) have become the drugs of choice to treat this pathology in pregnant women. Aim : to evaluate an effectiveness of preventing placenta-associated complications (PACs) in patients with recurrent miscarriage and circulating APAs. Materials and Methods . A prospective study was conducted to analyze the course of pregnancy and outcomes in 150 patients who had diagnostic APA titers and aggravated obstetric and gynecological anamnesis. All pregnant women received therapy with low-dose aspirin (LDA) and low molecular weight heparin (LMWHs). In addition to combining LMWHs and LDA, 126 (84.0 %) pregnant women received IVIG courses administered at gestational age of 6-8, 12-14, and 22-24 weeks. Results . Based on the data obtained, gestational complications such as chronic placental insufficiency, hemodynamic disorders, fetal growth retardation, gestational arterial hypertension, moderate preeclampsia (PE) were significantly more frequent in patients receiving no IVIG during pregnancy. It should be noted that development of severe obstetric complications, such as severe PE, premature detachment of a normally located placenta, massive blood loss, and antenatal fetal death were not observed in any case. No patient developed venous thromboembolism during pregnancy and in the postpartum period. Comparing relative expression area of annexin V, CD 34+, KiSS-peptine and its receptors (KiSS1R), there were revealed significant differences. The relative expression area for anticoagulant protein annexin V was 2.3-fold higher in IVIG-treated patients in pregnancy; endothelial marker CD34+ - 4-fold higher, KiSS-peptine - 2.3-fold higher, and KiSS1R - 5.4-fold higher in placenta from women treated with IVIG starting from early pregnancy stage. Conclusion . In order to assess the effectiveness of PAC prevention in patients with habitual miscarriage and circulating APAs, it is possible to estimate relative expression area for placental anticoagulant protein annexin V, endothelial marker CD 34+, KiSS-peptine and KiSS1R.
oligonucleotides
2026-03-26 | Present status of sFLT1 and PlGF as diagnostic and therapeutic targets for preeclampsia.
To review the current role of soluble fms-like tyrosine kinase-1 (sFLT1) and placental growth factor (PlGF) in the pathophysiology, diagnosis, prediction, and treatment of preeclampsia. Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide and has increased in prevalence in the United States. It is characterized by new-onset hypertension, proteinuria, and/or end-organ dysfunction, with early-onset disease often associated with placental ischemia, placental insufficiency, and fetal growth restriction. A central mechanism in preeclampsia is angiogenic imbalance, characterized by increased antiangiogenic factors, particularly sFLT1, and reduced proangiogenic signaling mediated by VEGF and PlGF. This review summarizes current evidence regarding sFLT1 biology, the clinical utility of the sFLT1/PlGF ratio, and emerging therapeutic strategies targeting sFLT1 in preeclampsia. sFLT1 is a soluble splice variant of VEGF receptor-1 that binds circulating VEGF and PlGF, thereby promoting endothelial dysfunction, vasoconstriction, and systemic manifestations of preeclampsia. The sFLT1/PlGF ratio has emerged as a clinically useful biomarker, particularly for short-term risk stratification in women with suspected preeclampsia, with strong negative predictive value for ruling out progression to severe disease within 1 to 2 weeks in appropriately selected patients. The ratio has been incorporated into clinical practice in multiple countries and was approved by the US Food and Drug Administration in 2023 for inpatient risk assessment in singleton pregnancies between 23 and 34 weeks and 6 days of gestation with hypertensive disorders of pregnancy. In parallel, therapeutic approaches targeting sFLT1, including small interfering RNA, antibodies, VEGF or PlGF-based molecular strategies, and apheresis, have shown promise in preclinical and early translational studies. sFLT1 is central to the pathophysiology of preeclampsia and has substantial clinical relevance as both a biomarker and a potential therapeutic target. The sFLT1/PlGF ratio is reshaping risk assessment and management of preeclampsia, while sFLT1-directed therapies may offer future disease-modifying treatment options. Further refinement of biomarker-guided use and therapeutic development is needed before broader implementation.
2025-02-05 | microRNA-Mediated Effects of Caloric Restriction on Trophoblast Invasion and Angiogenic Signaling in a Mouse Model of Fetal Growth Restriction
Trophoblast invasion is essential for normal placentation, with failure resulting in a fetal growth restriction (FGR) phenotype. Utilizing a calorie-restricted mouse model, we report progressive epigenetic, molecular, and phenotypic placental changes throughout gestation. Following maternal caloric restriction initiated at E9, we observed a significant reduction in fetal and placental weights beginning at E12.5, with persistent growth restriction at E14.5, E16.5, and E17.5. Immunohistochemistry of the decidual invasion site at E17.5 demonstrated reduced 1) decidual depth, 2) trophoblast invasion distance, and 3) trophoblast quantity within the decidua. Preceding these phenotypic changes, RT-qPCR revealed downregulation of trophoblast invasion and angiogenesis genes, including MMP2, MMP9, EFNA1, Rac1, Rras, ASCL2, TRAP2C, Prl7b1, VEGFa, VEGFb, PDGF, and AKT3, beginning as early as E14.5. Notably, microRNA sequencing at E12.5, prior to these transcriptional changes, identified significant upregulation of miR-503-5p, a predicted inhibitor of several of these pathways. The summation of these observations suggests miR-503-5p may be an early driver of placental dysfunction in FGR, linking maternal malnutrition to impaired trophoblast invasion and angiogenesis. These findings provide insight into the molecular mechanisms underlying placental insufficiency and highlight miR-503-5p as a potential therapeutic target for improving pregnancy outcomes in FGR.
2024-11-05 | Placental gene therapy in nonhuman primates: a pilot study of maternal, placental, and fetal response to non-viral, polymeric nanoparticle delivery of IGF1.
Currently, there are no placenta-targeted treatments to alter the in utero environment for administration to pregnant women who receive a diagnosis of fetal growth restriction (FGR). Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like growth factor 1 (IGF1) transgene to correct placental insufficiency in small animal models of FGR. Our goals were to extend these studies to a proof-of-concept study in the pregnant macaque, establish feasibility of nanoparticle-mediated gene therapy delivery to trophoblasts, and investigate the acute maternal, placental, and fetal responses to treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP- or IGF1-expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n = 1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4), and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using Western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transient transgene expression in villous syncytiotrophoblast. No off-target expression was observed in either maternal or fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4, and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 days after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent overactivity in the normal pregnancy environment. The lack of adverse maternal reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis, indicates no deleterious impact of treatment during the acute phase of study.
2024-03-14 | The Impact of SLC2A8 RNA Interference on Glucose Uptake and the Transcriptome of Human Trophoblast Cells.
While glucose is the primary fuel for fetal growth, the placenta utilizes the majority of glucose taken up from the maternal circulation. Of the facilitative glucose transporters in the placenta, SLC2A8 (GLUT8) is thought to primarily function as an intracellular glucose transporter; however, its function in trophoblast cells has not been determined. To gain insight into the function of SLC2A8 in the placenta, lentiviral-mediated RNA interference (RNAi) was performed in the human first-trimester trophoblast cell line ACH-3P. Non-targeting sequence controls (NTS RNAi; n = 4) and SLC2A8 RNAi (n = 4) infected ACH-3P cells were compared. A 79% reduction in SLC2A8 mRNA concentration was associated with an 11% reduction (p ≤ 0.05) in ACH-3P glucose uptake. NTS RNAi and SLC2A8 RNAi ACH-3P mRNA were subjected to RNAseq, identifying 1525 transcripts that were differentially expressed (|log2FC| > 1 and adjusted p-value < 0.05), with 273 transcripts derived from protein-coding genes, and the change in 10 of these mRNAs was validated by real-time qPCR. Additionally, there were 147 differentially expressed long non-coding RNAs. Functional analyses revealed differentially expressed genes involved in various metabolic pathways associated with cellular respiration, oxidative phosphorylation, and ATP synthesis. Collectively, these data indicate that SLC2A8 deficiency may impact placental uptake of glucose, but that its likely primary function in trophoblast cells is to support cellular respiration. Since the placenta oxidizes the majority of the glucose it takes up to support its own metabolic needs, impairment of SLC2A8 function could set the stage for functional placental insufficiency.
2024-01-04 | Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.
Currently, there are no placenta-targeted treatments to alter the in utero environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like 1 growth factor ( IGF1 ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated IGF1 treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( GFP- or IGF1- expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( GFP ; n =1), 48 h ( IGF1 ; n = 3) or 10 days ( IGF1 ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment. Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment. National Institutes of Health, and Wisconsin National Primate Research Center.
other
2026-02-12 | Regulatory T cells and decidual vascular remodelling - A new piece in the preeclampsia puzzle.
Improperly constrained inflammation at the placental-uterine interface is strongly implicated as a causal factor in preeclampsia. Inflammatory mediators and leukocytes in the decidua are key features of the underlying pathophysiology, with potential to cause uterine vascular anomalies that give rise to compromised placental function, particularly in the severe, early onet form of the disease. While uterine natural killer (uNK) cells are clearly involved, a critical question has been whether and how T cells might also contribute. Regulatory T (Treg) cells, immune-regulatory T cells that counteract inflammation and promote robust placentation, are commonly perturbed in preeclampsia, and systemic Treg cell insufficiency often precedes symptom onset. This review summarizes recent evidence from preclinical studies that collectively point to Treg cells as critical regulators of decidual spiral artery adaptation in early pregnancy, in part through modulating uNK cells. Transient depletion of Treg cells during early placental morphogenesis in mice causes fetal growth restriction and fetal loss associated with impaired remodeling of decidual spiral arteries, compromised uterine artery function, and uNK cell defects. Together with RNA sequencing data to evaluate the effects of Treg cell depletion on decidual biology, the findings provide compelling evidence to implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism involving regulation of uNK cells and trophoblast invasion. This new insight provides an important link between adaptive immune tolerance and spiral artery remodeling to better understand the origins of preeclampsia.
2026-01-10 | Applications of Exosomes in Female Medicine: A Systematic Review of Molecular Biology, Diagnostic and Therapeutic Perspectives.
Exosomes are nanoscale extracellular vesicles that mediate intercellular communication by transporting microRNAs, proteins, and lipids. Generated through Endosomal Sorting Complex Required for Transport (ESCRT)-dependent mechanisms or ESCRT-independent pathways, exosomes are released when multivesicular bodies fuse with the plasma membrane. The ESCRT-dependent pathway involves sequential protein complexes (ESCRT-0, I, II, III) that recognize and sort ubiquitinated cargo, induce membrane budding, and facilitate vesicle scission. In contrast, the ESCRT-independent pathway relies on membrane lipids such as ceramide and proteins like tetraspanins (CD9, CD63, CD81) to promote vesicle formation without ESCRT machinery. Furthermore, post-translational modifications, including ubiquitination, sumoylation, and phosphorylation, further serve as molecular switches, modulating the affinity of ESCRT complexes or cargo proteins for membrane domains and affecting ILV formation rates. In reproductive medicine, exosomes regulate oocyte maturation, embryo-endometrial crosstalk, placental development, and maternal-fetal communication. Altered exosomal signaling contributes to obstetric complications, including preeclampsia, gestational diabetes mellitus, and preterm birth, whereas distinct exosomal miRNA signatures serve as potential diagnostic biomarkers. In gynecology, dysregulated exosomes are implicated in endometriosis, polycystic ovary syndrome, premature ovarian insufficiency, and gynecological malignancies. In contrast, mesenchymal stem cell-derived exosomes show therapeutic promise in restoring ovarian function and enhancing fertility outcomes. The distinctive molecular profiles of circulating exosomes enable minimally invasive diagnosis, while their biocompatibility and ability to cross biological barriers position them as vehicles for targeted drug delivery. Characterization of accessible data provides non-invasive opportunities for disease monitoring. However, clinical translation faces challenges, including standardization of isolation protocols, establishment of reference ranges for biomarkers, and optimization of therapeutic dosing. This review summarizes exosome biogenesis, characterization methods, physiological functions, and clinical applications in obstetrics and gynecology, with an emphasis on their diagnostic and therapeutic potential. Future directions include large-scale biomarker validation studies, engineering approaches to enhance exosome targeting, and integration with precision medicine platforms to advance personalized reproductive healthcare.
2025-12-18 | Placental insufficiency causes fetal growth restriction in mice lacking Delta-like homologue 1
Abstract Fetal growth restriction (FGR) affects between 3-7% of pregnancies, is associated with increased perinatal morbidity and mortality, and linked to failure of placental function. The placenta is the key transient organ in pregnancy that directs nutrient transfer, intermediary metabolism and the production of hormones that drive maternal metabolic adaptations essential for pregnancy and lactation. The exchange surface of the placenta is formed in early development by the interaction between trophoblast cells that enclose the maternal blood and extraembryonic mesodermal cells that comprise the fetal vasculature. Despite recent insights into trophoblast development derived from novel in-vitro approaches, the processes driving extraembryonic mesoderm development are not well explored. This is due to a dearth of studies employing unbiased approaches to interrogate extraembryonic mesoderm cell populations. Here we use genetic labelling techniques to separate molecular events occurring in the trophoblast from those in the mesodermal layers of the placenta. In combination with conditional targeting, we show that the imprinted gene Dlk1 is a key player in providing nutrients to the embryo by controlling the placental surface area available for nutrient exchange, and by modulating the production of placental hormones that promote maternal nutrient provision in pregnancy.
2025-10-10 | Efficiency of ultrasound-guided placental gene therapy in a rabbit IUGR model and effects on offspring development.
Placental insufficiency is a major cause of intrauterine growth restriction (IUGR), and no effective prenatal therapy is currently available. Previous studies have demonstrated that gene therapies based on overexpression of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) can improve prenatal and postnatal development. Such therapies are mostly adenovirus-mediated, since adenoviral vectors are the most widely used vehicles for gene delivery due to their broad cellular tropism, ability to transduce non-dividing cells, and relative easiness of production and titration. Hence, this study evaluated the feasibility and safety of a novel minimally invasive ultrasound-guided intraplacental technique for the injection of adenoviral vectors encoding IGF-1 or VEGF in a rabbit model of IUGR, in which the condition was induced by maternal feed restriction to 50% of the average daily intake during gestation. Postnatal development was assessed through biometric measurements (body weight), metabolic profiling (lipid, carbohydrate, and protein metabolism), and histological cell counts in key organs. The results confirmed the marker expression by adenoviral vectors in all the treated fetuses and the absence of deleterious effects of the ultrasound-guided injection on the postnatal survival and growth of the offspring. The use of the technique for inducing both IGF-1 and VEGF over-expression by administration of adenoviral vectors in an IUGR model showed, in the case of VEGF, positive effects on the developmental and metabolic traits, with especial significance in the pulmonary and intestinal systems, of IUGR offspring. Hence, after further research, the proposed therapy may offer potential benefits in pregnancies with placental insufficiency and IUGR conditions.
2025-08-14 | Safety, immunogenicity and pregnancy outcomes in mothers and infants after vaccination with an adenovirus-vector COVID-19 vaccine during pregnancy.
COVID-19 during pregnancy can be associated with adverse pregnancy and infant outcomes. We assessed the safety, reactogenicity, and immunogenicity of maternal vaccination with Ad26.COV2.S COVID-19 vaccine and monitored serum and breast milk antibody levels in mothers and infants until 6 months post-delivery. This open-label Phase 2 study enrolled previously COVID-19 vaccinated or COVID-19-vaccine-naive healthy pregnant women in trimester two or three (NCT04765384). All women received a single dose of Ad26.COV2.S. Mothers and infants were followed-up for safety until 1-year post-partum and for immunogenicity, including antibodies in breast milk, until 6 months post-partum. Recruitment was stopped at 51 participants due to rapidity of roll-out of COVID-19 vaccines recommended during pregnancy. Ad26.COV2.S was well-tolerated regardless of previous COVID-19 vaccination history. All pregnancies resulted in a live infant, four were preterm. One serious adverse event of placental insufficiency Day-36 post-vaccination was considered vaccine-related by the investigator. One infant died due to complications associated with an unrelated ventricular septal defect. Ad26.COV2.S induced robust immune responses in women with different COVID-19 vaccination histories. Spike-binding antibody (SAbs) and virus neutralizing antibody (NAbs) titers at delivery tended to be higher in mothers vaccinated during trimester three. Maternal serum and cord blood were strongly correlated. 100% of infants had detectable SAbs at aged 6 months, and 70.6% had detectable NAbs, including 68.2% born to initially vaccine-naïve mothers. Maternal vaccination with an adenovirus-vector vaccine was well-tolerated and immunogenic in mothers and infants. These data could support the adoption of heterologous booster regimens during pregnancy and future adenovirus-vector vaccine development.
small molecules
2026-08-13 | Maternal Cardiovascular Phenotype in Fetal Growth Restriction with or Without Pre-Eclampsia: Insights from Echocardiography and Clinical Implications.
Fetal growth restriction (FGR) has traditionally been attributed to placental insufficiency. However, accumulating evidence suggests that maternal cardiovascular maladaptation contributes to disease expression, clinical heterogeneity, and long-term maternal cardiovascular risk. To review maternal echocardiographic findings in pregnancies complicated by FGR, with or without preeclampsia and to explore the role of cardiovascular phenotyping in risk stratification and clinical management. Narrative review of the current literature, including observational studies, systematic reviews, meta-analyses, and expert consensus statements on maternal hemodynamics and echocardiographic assessment in FGR. FGR is associated with a maladaptive cardiovascular profile characterized by reduced cardiac output, increased systemic vascular resistance and adverse cardiac remodeling. Echocardiography frequently identifies subclinical myocardial dysfunction, including impaired diastolic function and reduced global longitudinal strain despite preserved ejection fraction. Distinct maternal cardiovascular phenotypes emerge across the FGR spectrum, ranging from high-risk hypodynamic, resistance-dominant phenotypes to intermediate and low-risk phenotypes with preserved hemodynamic adaptation. Integration of maternal cardiovascular assessment with fetal Doppler findings may improve risk stratification and support phenotype-guided surveillance and therapeutic decision-making. Persistent postpartum cardiovascular abnormalities further support the concept of pregnancy as a cardiovascular stress test and identify women at increased long-term cardiovascular risk. FGR should be viewed as the clinical manifestation of a complex maternal-placental-cardiovascular interaction rather than an isolated placental disorder. Maternal cardiovascular phenotyping has the potential to refine risk stratification, support hemodynamic-guided management, and identify women who may benefit from structured long-term cardiovascular surveillance.
2026-07-11 | Complement as a driver of immune-vascular heterogeneity across preeclampsia subtypes: toward a precision medicine framework.
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, traditionally defined as a hypertensive disorder of pregnancy but increasingly recognized as a heterogeneous syndrome with diverse biological origins. Emerging evidence indicates that distinct pathogenic pathways-including placental insufficiency, maternal cardiometabolic dysfunction, and intrinsic immune dysregulation-contribute to different clinical phenotypes of the disease. Among these, the complement system has gained attention as a central regulator of immune-vascular interactions during pregnancy. Recent studies demonstrate that tightly controlled complement activation is required for normal placental development, whereas dysregulation of this system contributes to endothelial injury, inflammation, and microvascular dysfunction characteristic of PE. Importantly, complement activation patterns differ across disease subtypes: classical pathway activation predominates in placental-driven early-onset PE, chronic low-grade alternative pathway activation is associated with maternal metabolic disease, and genetic or functional defects in complement regulation define a subset of severe, complement-mediated cases with overlap features of thrombotic microangiopathy. Despite these advances, current diagnostic and therapeutic approaches remain largely non-specific and fail to account for this biological heterogeneity. Here, we propose a subtype-based framework of PE centered on complement dysregulation, integrating mechanistic, genetic, and clinical evidence. This model links distinct complement activation patterns to disease trajectories and identifies corresponding biomarker signatures and therapeutic targets. By redefining PE as a spectrum of complement-stratified disorders, this Review provides a conceptual foundation for precision diagnostics and mechanism-guided therapy. Such an approach has the potential to improve risk stratification, enable earlier detection, and support the development of targeted interventions tailored to individual disease mechanisms.
2026-06-29 | Vaginal microbiota in the first trimester of pregnancy and the development of placental insufficiency
Fetal growth restriction and preeclampsia, the underlying pathogenesis of which is placental insufficiency, are among the leading causes of perinatal and maternal morbidity and mortality worldwide. Objective. To study the association between vaginal microbiome and placental protein levels in the first trimester of pregnancy with the risk of developing of placental insufficiency. Material and methods. The study included 283 patients without history of obstetrical, gynecologic, or medical conditions. Each patient had their placental protein levels assessed-human chorionic gonadotropin (hCG) and placental-associated plasma protein A (PAPP-A) — based on the initial screening, and their vaginal microbiota in the first trimester of pregnancy was analyzed using polymerase chain reaction. Depending on whether placental insufficiency subsequently developed, all patients were divided into two groups: Group 1 — 203 patients without placental insufficiency; Group 2 — 80 patients whose pregnancy was complicated by the development of placental insufficiency. Results. Patients of Group 2 had statistically significant lower concentrations of placental proteins — hCG and PAPP-A — as well as higher levels of Gardnerella vaginalis, Prevotella bivia, Porphyromonas spp., and Eubacterium spp. — were detected in the first trimester of pregnancy compared to those in Group 1. According to the study results, with a PAPP-A MoM level ≤0.486 based on the first prenatal screening data and the number of Sneathia spp., Leptotrichia spp., and Fusobacterium spp. bacteria, A vaginal microbiota with ≤107.3 DNA copies is associated with a high risk of developing placental insufficiency. Conclusion. Patients with reduced levels of placental proteins based on the initial prenatal screening and higher numbers of opportunistic microorganisms in the first trimester of pregnancy have a higher risk of developing placental insufficiency in late gestation. Timely correction of the vaginal microbiota during the preconception period and early pregnancy may be an important way to prevent placental insufficiency.
2026-06-25 | USP22 suppresses trophoblast cell necroptosis in preeclampsia by stabilizing KAT2A-mediated histone acetylation at the SFRP1 promoter.
Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis. Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE. USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo. USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.
2026-06-01 | A perinatal approach for unraveling mitochondrial function in preeclampsia and fetal growth restriction: a role for mitochondrial-targeted therapies.
Preeclampsia (PE) is a complex hypertensive disorder resulting from placental insufficiency during pregnancy. PE contributes to maternal and fetal morbidity and mortality and often co-occurs with fetal growth restriction (FGR); these two are both considered placental insufficiency syndromes. Alterations in mitochondrial function levels due to placental insufficiency play an important role in the pathophysiology of PE and FGR. Changes in these processes can lead to maternal and fetal organ damage with subsequent risk to develop cardiovascular disease. This review therefore investigates the effects of placental insufficiency syndromes, including PE and FGR, on mitochondrial function and its underlying mechanisms, using a perinatal approach including maternal heart and kidney, placenta, and fetal heart and kidney. This review also explores the potential of mitochondrial-targeted therapies in mitigating these effects. We provide an overview of the literature at hand and demonstrate the critical role of mitochondrial function in different organ systems. Subsequently, we also discuss the need for mitochondrial-targeted therapies, in particular, focused on oxidative stress, metabolic pathways, mitochondrial quality control, and mitochondrial calcium handling. This knowledge provides guidance for future studies and potential therapies to improve PE and FGR and their consequences for maternal and fetal outcomes during pregnancy and cardiovascular health later in life.
proteins
2026-05-27 | The Contribution of Ultrasound and Doppler Studies on Impaired Intrauterine Conditions and the Development of Future Disease.
The Barker hypothesis links intrauterine conditions, mainly low birth weight, subject to poor nutrition with paradoxically improved standards of living and nutrition after World War II in Western countries, to adult disease, mainly coronary heart disease. The limitations of his hypothesis include the fact that it is based only on human epidemiological data and animal studies, and also that it is difficult to isolate the effect of the intrauterine environment from postnatal conditions, familial and genetic background. In the last 20 years, the introduction of ultrasound and Doppler techniques in the assessment of fetal and maternal vascularity added a major contribution to the evaluation of the intrauterine environment. Studies based on ultrasound and Doppler assist in differentiating between prematurity and fetal growth restriction (FGR), mainly in those with placental insufficiency, and postnatal morbidity and even mortality. In addition, the Pedersen hypothesis regarding fetuses with overgrowth, mainly with diabetic mothers, states that they are also prone to postnatal morbidity. However, most of the studies on the issue do not emphasize the effects of the intrauterine environment on fetal organs, such as the brain, heart, liver, kidneys and pancreas in FGR and fetal overgrowth, that may impose a different prognosis in later life. This narrative review aims to summarize current evidence from animal and human studies regarding the impact of intrauterine undernutrition and overnutrition on fetal organ development, and to evaluate how ultrasound and Doppler findings may contribute to understanding the link between the intrauterine environment and postnatal morbidity.
2026-05-19 | PATHOMORPHOLOGICAL AND IMMUNOHISTOCHEMICAL FEATURES OF CHRONIC PLACENTAL INSUFFICIENCY IN CONGENITAL INFECTIONS UNDER THE CONDITIONS OF KARAKALPAKSTAN
Chronic placental insufficiency (CPI) remains a critical obstetric complication, serving as a primary vector for intrauterine growth restriction, preterm birth, and perinatal mortality. In regions experiencing severe ecological degradation, such as the Republic of Karakalpakstan in the Aral Sea disaster zone, the etiology of CPI is profoundly compounded by environmental toxicity, high regional rates of maternal anemia, and the prevalent transmission of congenital (TORCH) infections. This comprehensive report investigates the synergistic impact of environmental factors and infectious agents on the pathomorphological and immunohistochemical (IHC) architecture of the human placenta. Utilizing advanced digital histomorphometry and computational image analysis, the study quantifies key biomarkers associated with angiogenesis (VEGF), cellular proliferation (Ki-67), apoptosis (Caspase-3), and localized inflammatory responses (CD68).
2026-04-29 | Placental hormones, IGF-1, and early-life growth: endocrine links between birth size and infant metabolic programming-a systematic review.
The purpose of this study is to systematically review human evidence linking placental hormones and IGF-1 with fetal growth, birth size, and early-life metabolic programming, and to identify disease-specific translational signals relevant to fetal growth restriction, metabolically complicated pregnancy, and extreme prematurity. A systematic review of PubMed and Scopus was performed for human studies published from January 2000 to March 2025. Eligible studies examined placental growth hormone, human placental lactogen, placental IGF-axis markers, or related stress-hormone pathways in relation to birth size, fetal or infant growth, or early metabolic outcomes. Reporting was aligned with PRISMA 2020. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I principles for observational studies. Because of substantial clinical and methodological heterogeneity, findings were synthesized narratively. Thirty-seven included studies showed that mid-gestation placental growth hormone had the most consistent positive associations with fetal growth and birth size, whereas early placental growth hormone was less informative. Cord blood IGF-1 was the most reproducible endocrine correlate of birth length and weight. Reduced maternal or placental lactogen signals and lower placental 11β-HSD2 activity clustered with placental insufficiency and fetal growth restriction, while diabetic pregnancies showed a shift toward adiposity-related outcomes. In extreme prematurity, abrupt loss of placental endocrine support created a translational window in which rhIGF-1/rhIGFBP-3 replacement emerged as the clearest mechanism-based intervention, although current clinical evidence remains preliminary. Placental endocrine markers should not be used as standalone screening tools. Their main value at present is mechanistic and translational: combined hormone patterns may refine biological understanding and risk stratification within defined maternal and neonatal disease frameworks, while IGF-1 replacement in extreme prematurity represents the most credible current therapeutic lead. • Placental hormones and IGF-1 are linked with fetal growth, birth size, and neonatal metabolic adaptation, but 45 published evidence is heterogeneous and clinically fragmented. • This systematic review organizes the human data within fetal growth restriction, diabetic/LGA pregnancy, and extreme prematurity frameworks and identifies translational signals-especially early IGF-1 replacement in extreme prematurity-rather than standalone diagnostic biomarkers.
2026-03-28 | The Impact of Fetal Growth Restriction on Myocardial Development from Fetal Life to Early Childhood: A Narrative Review.
Background/Objectives: Fetal growth restriction (FGR), historically termed intrauterine growth restriction (IUGR), is a multifactorial condition in which the fetus fails to reach its genetically determined growth potential, most often due to placental insufficiency. Beyond its link with increased perinatal morbidity and mortality, FGR has been associated with long-term cardiovascular risk through early-life programming. The developing fetal heart is vulnerable to chronic hypoxia and nutrient deprivation, potentially inducing structural and functional alterations with lifelong consequences. This narrative review summarizes and critically appraises experimental and clinical evidence on the impact of FGR on myocardial development and cardiovascular health from fetal life to adulthood. Methods: We conducted a narrative review using a structured literature search of studies published in the last 15 years in PubMed and Scopus, focusing on experimental, imaging, and epidemiological research evaluating cardiac structure, function, and long-term cardiovascular outcomes in FGR. Evidence from fetal and neonatal echocardiography, including Doppler and speckle-tracking techniques, as well as molecular and histological studies, was examined. No statistical meta-analysis was performed. Results: FGR has been associated with reduced cardiomyocyte number, altered myocardial architecture, increased interstitial fibrosis, and persistent ventricular remodeling. Functional studies suggest early impairments in systolic and diastolic performance, with alterations in cardiac energy metabolism and epigenetic regulation. Advanced imaging may enable detection of subclinical cardiac dysfunction in utero and early postnatally. Epidemiological data suggest an increased risk of hypertension, ischemic heart disease, heart failure, and metabolic disorders in adulthood among individuals born growth-restricted. Conclusions: FGR represents an early cardiovascular risk condition. Improved understanding of fetal cardiac programming may help refine risk stratification, surveillance, and preventive strategies to reduce long-term cardiovascular morbidity in individuals born growth-restricted.
2026-03-11 | Insights from animal models: Dissecting the independent roles of oxygen and nutrients in the fetal origins of cardiovascular disease.
Depending on the pregnancy complication, substrate delivery to a developing fetus can be reduced, changing the course of fetal growth below the genetically determined in utero growth potential, resulting in fetal growth restriction (FGR). FGR is linked to an increased risk of developing cardiovascular disease (CVD) in later life. When caused by placental insufficiency, FGR is characterized by fetal hypoxaemia and hypoglycaemia due to reduced substrate supply to the fetus. However, other common pregnancy complications exist, where fetal hypoxaemia or hypoglycaemia may or may not occur. It is therefore necessary to understand the independent and synergistic contributions of hypoxaemia and hypoglycaemia to the fetal origins of CVD. In doing so, this knowledge will aid in the development of intervention strategies. The aim of this review is to provide mechanistic insights by comparing findings across different paradigms of developmental programming using animal models of FGR, with consideration of the timing, duration, and severity of the insult, and the ventricles and fetal sex studied.
antibodies
2026-03-12 | Predicting chronic placental insufficiency in patients with a complicated obstetric history at pregnancy planning stage
Introduction. Chronic placental insufficiency (CPI) is one of the leading causes of fetal growth restriction (FGR), perinatal loss, and complicated pregnancy. Currently, no validated methods for predicting CPI during pregnancy planning are available, which complicates high-risk patient stratification early and enabling timely prevention. Aim: to develop a mathematical model for predicting CPI risk in women with a complicated obstetric history at the pre-pregnancy preparation stage. Materials and Methods . A retrospective clinical study assessing 462 patients with a complicated obstetric history was conducted. The outcomes of previous pregnancies, concomitant extragenital diseases, circulation of criterial (anti-β2glycoprotein and anti-cardiolipin antibodies, lupus anticoagulant) and non-criterial (anti-annexin 5, anti-phosphatidylserine, anti-phosphatidylinositol, anti-prothrombin, anti-human chorionic gonadotropin) antiphospholipid antibodies (APA), indicators of lymphocyte subpopulation composition, coagulation profile, and genetic thrombophilia were evaluated. Enzyme-linked immunosorbent assay, flow cytometry, ultrasound, and histological diagnostics were used. Binary logistic regression was applied to construct a prognostic model, and the diagnostic significance of the indicators was assessed using ROC curves. Results. Detected APA high titers and/or lupus anticoagulant were associated with significantly elevated CPI incidence (63.1% vs. 4.6%; p < 0.001) and FGR (43.4% vs. 4.6%; p < 0.001). Immunological imbalance (increased percentage of B-lymphocytes and NK cells) increased CPI risk by 1.3–5.5 times. The constructed prediction model, which included indicators of immunological activity and comorbidity, demonstrated high accuracy: AUC = 0.89, sensitivity 85.7%, specificity 85.7%. Conclusion. The developed mathematical model allows for highly accurate prediction of CPI risk developing in women with a complicated obstetric history even before pregnancy, which opens up avenues for personalized selection of preventive measures, including immunomodulatory therapy and dynamic monitoring, and contributes to lowering frequency of perinatal complications.
2025-12-12 | Immune-mediated mechanisms and maternal-fetal interface dysfunction in obstetric antiphospholipid syndrome.
Obstetric antiphospholipid syndrome (OAPS) is a complex autoimmune disorder that significantly compromises pregnancy, manifesting as recurrent miscarriage, stillbirth, placental insufficiency, and preeclampsia. Its increasing prevalence underscores the pressing need to elucidate its multifaceted pathogenic mechanisms to improve maternal and fetal outcomes. While traditionally attributed to thrombosis driven by antiphospholipid antibodies (aPL), emerging evidence indicates that OAPS can disrupt placental perfusion, impair trophoblast proliferation and invasion, and compromise placental angiogenesis even in the absence of overt thrombotic events. Beyond direct effects on trophoblasts and vascular remodeling, aPLs profoundly perturb the immune milieu at the maternal-fetal interface, encompassing complement activation, excessive formation of neutrophil extracellular traps (NETs), dysfunction of decidual natural killer cells and macrophages, and dysregulated B cell responses. These immune-mediated alterations collectively establish a sustained pro-inflammatory environment that undermines placental development and predisposes to adverse pregnancy outcomes. This review provides a comprehensive synthesis of the immunopathogenic mechanisms of OAPS that extend beyond thrombosis, and emphasizes the intricate crosstalk between immune cells and the complement-NET axis. A deeper understanding of these immune-mediated pathways may inform the development of targeted therapeutic strategies to optimize maternal and fetal outcomes in affected pregnancies.
2025-06-30 | Chronic Histiocytic Intervillositis: Insights into Immunopathogenesis and Prospective Treatments
Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory disorder associated with adverse pregnancy outcomes, including fetal growth restriction, miscarriage, and stillbirth. Its diagnosis is made retrospectively via histopathology, limiting timely intervention. This review explores the emerging hypothesis that CHI is an alloimmune condition resulting from aberrant maternal immune responses to paternally derived fetal antigens. Key findings from current literature include perivillous fibrin deposition and maternal histiocyte accumulation in the placental intervillous space, both of which disrupt maternal–fetal exchange. Additional evidence points to complement activation, particularly C4d and C5b-9 deposition, increased CD8+ T cell infiltration, and inflammasome pathway involvement, all contributing to placental insufficiency. The role of anti-HLA antibodies remains under investigation, with conflicting data on their presence and clinical significance. However, abnormal HLA class II expression on the syncytiotrophoblast in CHI may facilitate maternal alloimmune recognition and antibody production. Current treatments, including anticoagulants and immunosuppressants, show limited efficacy, and no standardised management exists. The findings underscore a critical need for prospective studies, biomarker discovery, and targeted immunomodulatory therapies. Improved understanding of CHI pathogenesis may facilitate earlier diagnosis, personalised treatment, and prevention of recurrence and primary disease in future pregnancies.
2025-06-08 | Certolizumab pegol to prevent adverse pregnancy outcomes in patients with antiphospholipid syndrome and lupus anticoagulant (IMPACT): results of a prospective, single-arm, open-label, phase 2 trial.
The aim of this study was to evaluate whether certolizumab pegol, a tumour necrosis factor α inhibitor with little or no transport across the placenta, added to standard treatment with low molecular weight heparin plus low dose aspirin, reduces rates of adverse pregnancy outcome (APO) in high-risk pregnancies with antiphospholipid syndrome (APS). We assessed treatment with certolizumab in pregnant patients with APS and lupus anticoagulant, administered gestational weeks 8 through 28, in addition to standard treatment. The primary APO was a composite of fetal death ≥10 weeks' gestation or pre-eclampsia with severe features or placental insufficiency requiring delivery <34 weeks' gestation. Target sample size was 45 with expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively observed population of similarly managed APS pregnancies. Fifty-one patients were enrolled, and 9 had primary APO (17.6%; 95% CI, 8.4%-30.9%). Excluding 6 patients who had a pregnancy loss <10 weeks' gestation or fetal loss due to genetic abnormalities, primary APO occurred in 9 of the 45 patients (20%; 95% CI, 9.6%-34.6%), meeting predetermined criteria for efficacy of certolizumab and significantly lower than rates in historical controls. Median gestational age at delivery in certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of pre-eclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections and no new cases or severe flares of lupus. Certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.
2024-09-12 | Assessing the effectiveness of preventing placenta-associated complications in patients with burdened obstetric history and circulating antiphospholipid antibodies
Introduction . The role of antiphospholipid antibody (APA) carriage in the pathogenesis of pregnancy failure is one of the most recently debated issues. To date, no unified therapeutic approach to immunotherapy of antiphospholipid syndrome (APS) in pregnancy exists. Intravenous immunoglobulins (IVIG) have become the drugs of choice to treat this pathology in pregnant women. Aim : to evaluate an effectiveness of preventing placenta-associated complications (PACs) in patients with recurrent miscarriage and circulating APAs. Materials and Methods . A prospective study was conducted to analyze the course of pregnancy and outcomes in 150 patients who had diagnostic APA titers and aggravated obstetric and gynecological anamnesis. All pregnant women received therapy with low-dose aspirin (LDA) and low molecular weight heparin (LMWHs). In addition to combining LMWHs and LDA, 126 (84.0 %) pregnant women received IVIG courses administered at gestational age of 6-8, 12-14, and 22-24 weeks. Results . Based on the data obtained, gestational complications such as chronic placental insufficiency, hemodynamic disorders, fetal growth retardation, gestational arterial hypertension, moderate preeclampsia (PE) were significantly more frequent in patients receiving no IVIG during pregnancy. It should be noted that development of severe obstetric complications, such as severe PE, premature detachment of a normally located placenta, massive blood loss, and antenatal fetal death were not observed in any case. No patient developed venous thromboembolism during pregnancy and in the postpartum period. Comparing relative expression area of annexin V, CD 34+, KiSS-peptine and its receptors (KiSS1R), there were revealed significant differences. The relative expression area for anticoagulant protein annexin V was 2.3-fold higher in IVIG-treated patients in pregnancy; endothelial marker CD34+ - 4-fold higher, KiSS-peptine - 2.3-fold higher, and KiSS1R - 5.4-fold higher in placenta from women treated with IVIG starting from early pregnancy stage. Conclusion . In order to assess the effectiveness of PAC prevention in patients with habitual miscarriage and circulating APAs, it is possible to estimate relative expression area for placental anticoagulant protein annexin V, endothelial marker CD 34+, KiSS-peptine and KiSS1R.
oligonucleotides
2026-03-26 | Present status of sFLT1 and PlGF as diagnostic and therapeutic targets for preeclampsia.
To review the current role of soluble fms-like tyrosine kinase-1 (sFLT1) and placental growth factor (PlGF) in the pathophysiology, diagnosis, prediction, and treatment of preeclampsia. Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide and has increased in prevalence in the United States. It is characterized by new-onset hypertension, proteinuria, and/or end-organ dysfunction, with early-onset disease often associated with placental ischemia, placental insufficiency, and fetal growth restriction. A central mechanism in preeclampsia is angiogenic imbalance, characterized by increased antiangiogenic factors, particularly sFLT1, and reduced proangiogenic signaling mediated by VEGF and PlGF. This review summarizes current evidence regarding sFLT1 biology, the clinical utility of the sFLT1/PlGF ratio, and emerging therapeutic strategies targeting sFLT1 in preeclampsia. sFLT1 is a soluble splice variant of VEGF receptor-1 that binds circulating VEGF and PlGF, thereby promoting endothelial dysfunction, vasoconstriction, and systemic manifestations of preeclampsia. The sFLT1/PlGF ratio has emerged as a clinically useful biomarker, particularly for short-term risk stratification in women with suspected preeclampsia, with strong negative predictive value for ruling out progression to severe disease within 1 to 2 weeks in appropriately selected patients. The ratio has been incorporated into clinical practice in multiple countries and was approved by the US Food and Drug Administration in 2023 for inpatient risk assessment in singleton pregnancies between 23 and 34 weeks and 6 days of gestation with hypertensive disorders of pregnancy. In parallel, therapeutic approaches targeting sFLT1, including small interfering RNA, antibodies, VEGF or PlGF-based molecular strategies, and apheresis, have shown promise in preclinical and early translational studies. sFLT1 is central to the pathophysiology of preeclampsia and has substantial clinical relevance as both a biomarker and a potential therapeutic target. The sFLT1/PlGF ratio is reshaping risk assessment and management of preeclampsia, while sFLT1-directed therapies may offer future disease-modifying treatment options. Further refinement of biomarker-guided use and therapeutic development is needed before broader implementation.
2025-02-05 | microRNA-Mediated Effects of Caloric Restriction on Trophoblast Invasion and Angiogenic Signaling in a Mouse Model of Fetal Growth Restriction
Trophoblast invasion is essential for normal placentation, with failure resulting in a fetal growth restriction (FGR) phenotype. Utilizing a calorie-restricted mouse model, we report progressive epigenetic, molecular, and phenotypic placental changes throughout gestation. Following maternal caloric restriction initiated at E9, we observed a significant reduction in fetal and placental weights beginning at E12.5, with persistent growth restriction at E14.5, E16.5, and E17.5. Immunohistochemistry of the decidual invasion site at E17.5 demonstrated reduced 1) decidual depth, 2) trophoblast invasion distance, and 3) trophoblast quantity within the decidua. Preceding these phenotypic changes, RT-qPCR revealed downregulation of trophoblast invasion and angiogenesis genes, including MMP2, MMP9, EFNA1, Rac1, Rras, ASCL2, TRAP2C, Prl7b1, VEGFa, VEGFb, PDGF, and AKT3, beginning as early as E14.5. Notably, microRNA sequencing at E12.5, prior to these transcriptional changes, identified significant upregulation of miR-503-5p, a predicted inhibitor of several of these pathways. The summation of these observations suggests miR-503-5p may be an early driver of placental dysfunction in FGR, linking maternal malnutrition to impaired trophoblast invasion and angiogenesis. These findings provide insight into the molecular mechanisms underlying placental insufficiency and highlight miR-503-5p as a potential therapeutic target for improving pregnancy outcomes in FGR.
2024-11-05 | Placental gene therapy in nonhuman primates: a pilot study of maternal, placental, and fetal response to non-viral, polymeric nanoparticle delivery of IGF1.
Currently, there are no placenta-targeted treatments to alter the in utero environment for administration to pregnant women who receive a diagnosis of fetal growth restriction (FGR). Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like growth factor 1 (IGF1) transgene to correct placental insufficiency in small animal models of FGR. Our goals were to extend these studies to a proof-of-concept study in the pregnant macaque, establish feasibility of nanoparticle-mediated gene therapy delivery to trophoblasts, and investigate the acute maternal, placental, and fetal responses to treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP- or IGF1-expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n = 1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4), and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using Western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transient transgene expression in villous syncytiotrophoblast. No off-target expression was observed in either maternal or fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4, and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 days after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent overactivity in the normal pregnancy environment. The lack of adverse maternal reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis, indicates no deleterious impact of treatment during the acute phase of study.
2024-03-14 | The Impact of SLC2A8 RNA Interference on Glucose Uptake and the Transcriptome of Human Trophoblast Cells.
While glucose is the primary fuel for fetal growth, the placenta utilizes the majority of glucose taken up from the maternal circulation. Of the facilitative glucose transporters in the placenta, SLC2A8 (GLUT8) is thought to primarily function as an intracellular glucose transporter; however, its function in trophoblast cells has not been determined. To gain insight into the function of SLC2A8 in the placenta, lentiviral-mediated RNA interference (RNAi) was performed in the human first-trimester trophoblast cell line ACH-3P. Non-targeting sequence controls (NTS RNAi; n = 4) and SLC2A8 RNAi (n = 4) infected ACH-3P cells were compared. A 79% reduction in SLC2A8 mRNA concentration was associated with an 11% reduction (p ≤ 0.05) in ACH-3P glucose uptake. NTS RNAi and SLC2A8 RNAi ACH-3P mRNA were subjected to RNAseq, identifying 1525 transcripts that were differentially expressed (|log2FC| > 1 and adjusted p-value < 0.05), with 273 transcripts derived from protein-coding genes, and the change in 10 of these mRNAs was validated by real-time qPCR. Additionally, there were 147 differentially expressed long non-coding RNAs. Functional analyses revealed differentially expressed genes involved in various metabolic pathways associated with cellular respiration, oxidative phosphorylation, and ATP synthesis. Collectively, these data indicate that SLC2A8 deficiency may impact placental uptake of glucose, but that its likely primary function in trophoblast cells is to support cellular respiration. Since the placenta oxidizes the majority of the glucose it takes up to support its own metabolic needs, impairment of SLC2A8 function could set the stage for functional placental insufficiency.
2024-01-04 | Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.
Currently, there are no placenta-targeted treatments to alter the in utero environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like 1 growth factor ( IGF1 ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated IGF1 treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( GFP- or IGF1- expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( GFP ; n =1), 48 h ( IGF1 ; n = 3) or 10 days ( IGF1 ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment. Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment. National Institutes of Health, and Wisconsin National Primate Research Center.
other
2026-02-12 | Regulatory T cells and decidual vascular remodelling - A new piece in the preeclampsia puzzle.
Improperly constrained inflammation at the placental-uterine interface is strongly implicated as a causal factor in preeclampsia. Inflammatory mediators and leukocytes in the decidua are key features of the underlying pathophysiology, with potential to cause uterine vascular anomalies that give rise to compromised placental function, particularly in the severe, early onet form of the disease. While uterine natural killer (uNK) cells are clearly involved, a critical question has been whether and how T cells might also contribute. Regulatory T (Treg) cells, immune-regulatory T cells that counteract inflammation and promote robust placentation, are commonly perturbed in preeclampsia, and systemic Treg cell insufficiency often precedes symptom onset. This review summarizes recent evidence from preclinical studies that collectively point to Treg cells as critical regulators of decidual spiral artery adaptation in early pregnancy, in part through modulating uNK cells. Transient depletion of Treg cells during early placental morphogenesis in mice causes fetal growth restriction and fetal loss associated with impaired remodeling of decidual spiral arteries, compromised uterine artery function, and uNK cell defects. Together with RNA sequencing data to evaluate the effects of Treg cell depletion on decidual biology, the findings provide compelling evidence to implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism involving regulation of uNK cells and trophoblast invasion. This new insight provides an important link between adaptive immune tolerance and spiral artery remodeling to better understand the origins of preeclampsia.
2026-01-10 | Applications of Exosomes in Female Medicine: A Systematic Review of Molecular Biology, Diagnostic and Therapeutic Perspectives.
Exosomes are nanoscale extracellular vesicles that mediate intercellular communication by transporting microRNAs, proteins, and lipids. Generated through Endosomal Sorting Complex Required for Transport (ESCRT)-dependent mechanisms or ESCRT-independent pathways, exosomes are released when multivesicular bodies fuse with the plasma membrane. The ESCRT-dependent pathway involves sequential protein complexes (ESCRT-0, I, II, III) that recognize and sort ubiquitinated cargo, induce membrane budding, and facilitate vesicle scission. In contrast, the ESCRT-independent pathway relies on membrane lipids such as ceramide and proteins like tetraspanins (CD9, CD63, CD81) to promote vesicle formation without ESCRT machinery. Furthermore, post-translational modifications, including ubiquitination, sumoylation, and phosphorylation, further serve as molecular switches, modulating the affinity of ESCRT complexes or cargo proteins for membrane domains and affecting ILV formation rates. In reproductive medicine, exosomes regulate oocyte maturation, embryo-endometrial crosstalk, placental development, and maternal-fetal communication. Altered exosomal signaling contributes to obstetric complications, including preeclampsia, gestational diabetes mellitus, and preterm birth, whereas distinct exosomal miRNA signatures serve as potential diagnostic biomarkers. In gynecology, dysregulated exosomes are implicated in endometriosis, polycystic ovary syndrome, premature ovarian insufficiency, and gynecological malignancies. In contrast, mesenchymal stem cell-derived exosomes show therapeutic promise in restoring ovarian function and enhancing fertility outcomes. The distinctive molecular profiles of circulating exosomes enable minimally invasive diagnosis, while their biocompatibility and ability to cross biological barriers position them as vehicles for targeted drug delivery. Characterization of accessible data provides non-invasive opportunities for disease monitoring. However, clinical translation faces challenges, including standardization of isolation protocols, establishment of reference ranges for biomarkers, and optimization of therapeutic dosing. This review summarizes exosome biogenesis, characterization methods, physiological functions, and clinical applications in obstetrics and gynecology, with an emphasis on their diagnostic and therapeutic potential. Future directions include large-scale biomarker validation studies, engineering approaches to enhance exosome targeting, and integration with precision medicine platforms to advance personalized reproductive healthcare.
2025-12-18 | Placental insufficiency causes fetal growth restriction in mice lacking Delta-like homologue 1
Abstract Fetal growth restriction (FGR) affects between 3-7% of pregnancies, is associated with increased perinatal morbidity and mortality, and linked to failure of placental function. The placenta is the key transient organ in pregnancy that directs nutrient transfer, intermediary metabolism and the production of hormones that drive maternal metabolic adaptations essential for pregnancy and lactation. The exchange surface of the placenta is formed in early development by the interaction between trophoblast cells that enclose the maternal blood and extraembryonic mesodermal cells that comprise the fetal vasculature. Despite recent insights into trophoblast development derived from novel in-vitro approaches, the processes driving extraembryonic mesoderm development are not well explored. This is due to a dearth of studies employing unbiased approaches to interrogate extraembryonic mesoderm cell populations. Here we use genetic labelling techniques to separate molecular events occurring in the trophoblast from those in the mesodermal layers of the placenta. In combination with conditional targeting, we show that the imprinted gene Dlk1 is a key player in providing nutrients to the embryo by controlling the placental surface area available for nutrient exchange, and by modulating the production of placental hormones that promote maternal nutrient provision in pregnancy.
2025-10-10 | Efficiency of ultrasound-guided placental gene therapy in a rabbit IUGR model and effects on offspring development.
Placental insufficiency is a major cause of intrauterine growth restriction (IUGR), and no effective prenatal therapy is currently available. Previous studies have demonstrated that gene therapies based on overexpression of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) can improve prenatal and postnatal development. Such therapies are mostly adenovirus-mediated, since adenoviral vectors are the most widely used vehicles for gene delivery due to their broad cellular tropism, ability to transduce non-dividing cells, and relative easiness of production and titration. Hence, this study evaluated the feasibility and safety of a novel minimally invasive ultrasound-guided intraplacental technique for the injection of adenoviral vectors encoding IGF-1 or VEGF in a rabbit model of IUGR, in which the condition was induced by maternal feed restriction to 50% of the average daily intake during gestation. Postnatal development was assessed through biometric measurements (body weight), metabolic profiling (lipid, carbohydrate, and protein metabolism), and histological cell counts in key organs. The results confirmed the marker expression by adenoviral vectors in all the treated fetuses and the absence of deleterious effects of the ultrasound-guided injection on the postnatal survival and growth of the offspring. The use of the technique for inducing both IGF-1 and VEGF over-expression by administration of adenoviral vectors in an IUGR model showed, in the case of VEGF, positive effects on the developmental and metabolic traits, with especial significance in the pulmonary and intestinal systems, of IUGR offspring. Hence, after further research, the proposed therapy may offer potential benefits in pregnancies with placental insufficiency and IUGR conditions.
2025-08-14 | Safety, immunogenicity and pregnancy outcomes in mothers and infants after vaccination with an adenovirus-vector COVID-19 vaccine during pregnancy.
COVID-19 during pregnancy can be associated with adverse pregnancy and infant outcomes. We assessed the safety, reactogenicity, and immunogenicity of maternal vaccination with Ad26.COV2.S COVID-19 vaccine and monitored serum and breast milk antibody levels in mothers and infants until 6 months post-delivery. This open-label Phase 2 study enrolled previously COVID-19 vaccinated or COVID-19-vaccine-naive healthy pregnant women in trimester two or three (NCT04765384). All women received a single dose of Ad26.COV2.S. Mothers and infants were followed-up for safety until 1-year post-partum and for immunogenicity, including antibodies in breast milk, until 6 months post-partum. Recruitment was stopped at 51 participants due to rapidity of roll-out of COVID-19 vaccines recommended during pregnancy. Ad26.COV2.S was well-tolerated regardless of previous COVID-19 vaccination history. All pregnancies resulted in a live infant, four were preterm. One serious adverse event of placental insufficiency Day-36 post-vaccination was considered vaccine-related by the investigator. One infant died due to complications associated with an unrelated ventricular septal defect. Ad26.COV2.S induced robust immune responses in women with different COVID-19 vaccination histories. Spike-binding antibody (SAbs) and virus neutralizing antibody (NAbs) titers at delivery tended to be higher in mothers vaccinated during trimester three. Maternal serum and cord blood were strongly correlated. 100% of infants had detectable SAbs at aged 6 months, and 70.6% had detectable NAbs, including 68.2% born to initially vaccine-naïve mothers. Maternal vaccination with an adenovirus-vector vaccine was well-tolerated and immunogenic in mothers and infants. These data could support the adoption of heterologous booster regimens during pregnancy and future adenovirus-vector vaccine development.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Placental insufficiency.
1 orphan drug designation for Placental insufficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adenoviral vector serotype 5 containing the vascular endothelial growth factor D isoform (preprocessed short form) from a CMV promoter | gene therapies | EMA | 2015-01-15 | — | Magnus Invention Management Ltd |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.