Search Results (100)

Background/Objectives: Preeclampsia is associated with endothelial dysfunction and neurological morbidity. Non-invasive ocular imaging may offer insight into subclinical ocular changes associated with neurological involvement. This prospective single-center pilot study evaluated retinal nerve fiber layer (RNFL) thickness, optic nerve sheath diameter (ONSD), and angiogenic biomarkers in women with and without preeclampsia across the peripartum period. Methods: Pregnant women with preeclampsia and normotensive controls were enrolled at a tertiary center. RNFL thickness was assessed by optical coherence tomography and ONSD by transbulbar ultrasound at three predefined visits: antepartum, early postpartum, and late postpartum. The soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio was determined at the antepartum visit. Group comparisons, longitudinal changes, and exploratory correlations were analyzed, with paired-eye dependence addressed using generalized estimating equations (GEE). Results: Thirty-eight women were included; after reclassification of three controls who developed preeclampsia, 15 women were analyzed in the preeclampsia group and 23 in the control group. RNFL thickness was numerically higher in women with preeclampsia across visits; GEE analyses accounting for paired-eye measurements showed exploratory between-group differences at the early postpartum visit. ONSD did not differ significantly between groups, and no participant had a bilateral mean ONSD > 5.8 mm. No significant between-group differences in longitudinal change from early to late postpartum were observed. Exploratory analyses did not demonstrate a consistent association between the sFlt-1/PlGF ratio and the imaging parameters. Conclusions: RNFL thickness was numerically higher in women with preeclampsia, whereas ONSD showed no clear separation between groups. The findings remain exploratory and do not establish a diagnostic or prognostic role for either imaging parameter. Larger prospective studies are needed to determine the clinical relevance of non-invasive ocular imaging in preeclampsia. Full article

Background and Objectives: Pre-eclampsia (PE) is an obstetric complication defined by placental insufficiency, including intrauterine growth restriction and placental abruption. Timely and accurate detection and treatment of pre-eclampsia are difficult because its diagnostic criteria are still based on nonspecific signs and symptoms and because the association between common severity criteria, and unfavorable outcomes for mother and fetus remain unclear. Therefore, the aim of this study was to evaluate the potential use of blood and urine PE risk markers—soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), sFlt-1/PlGF ratio, and albumin/creatin ratio—in predicting and managing PE in groups at risk for preterm and term PE (gestational weeks 24–37) and to correlate the levels of blood and urine PE markers with pregnancy outcome indicators. Materials and Methods: This study was conducted at the Department of Obstetrics and Gynecology and at the Center of Laboratory Diagnostics and Nuclear Medicine, University Clinical Center of Vojvodina. This study included 166 pregnant women (GW 24–37) divided into two groups: study group P (n = 52), consisting of pregnant women who were identified as a high-risk group for PE according to clinical signs and medical history and who subsequently developed PE; control group C (n = 114), consisting of pregnant women who had risk factors in their medical history but did not eventually develop PE symptoms. The evaluated parameters included two groups: blood and urine PE risk indicators—biochemical markers such as PlGF, sFlt-1, and sFlt-1/PlGF ratio; urine risk indicators such as albumin/creatine ratio; and pregnancy outcome indicators—gestational age of delivery (GW) and neonatal birth weight (NW). Results: The results of the analysis support that the PE risk biochemical indicators (PlGF, sFlt-1, sFlt-1/PlGF ratio, and albumin/creatine ratio) show statistically significant differences between the analyzed groups, that they correlate with PE occurrence, and that they have good predictive value. As expected, sFlt-1/PlGF ratio and albumin/creatine ratio, as the most valuable PE risk indicators, show good predictive value. However, our results also demonstrate that pro- and antiangiogenic indicators alone, especially sFlt-1 (high values), may play roles in risk evaluation and prediction of preterm and term PE (GW 24–37). Conclusions: In our study, all evaluated blood and urine indicators (PlGF, sFlt-1, sFlt-1/PlGF ratio, and albumin/creatine ratio) show high predictive value for PE in a PE risk group of pregnancies between GW 24 and 37. The results suggest that sFlt-1 alone has equal predictive value to sFlt-1/PlGF ratio and outperformed PlGF in predicting PE onset. The combined use of pro- and antiangiogenic biochemical markers, indices, and urine markers in blood, together with patient history and clinical parameters, shows potential as a more effective means of predicting PE than a single biochemical parameter such as sFlt-1/PlGF ratio. Full article

Background/Objectives: Hypertensive disorders of pregnancy (HDPs) such as preeclampsia are associated with adverse maternal and perinatal outcomes and related to high soluble fms-like tyrosine kinase-1 (sFlt-1) levels and low placental growth factor (PlGF) levels. While these biomarkers are used for predicting and diagnosing preeclampsia, their impact on postnatal neonatal nutritional management, growth, and body composition is not well-established. Therefore, we aimed to evaluate the association between maternal angiogenic markers, neonatal growth, and body composition. Methods: This study represents a secondary analysis of a prospective cohort study conducted at the Medical University of Vienna. Women with HDP were included in the analysis, and infants were stratified by gestational age at birth into preterm (<37 weeks of gestation) and term (≥37 weeks of gestation) groups. Maternal angiogenic markers were routinely measured at the time when HDP was first suspected, and neonatal body composition was assessed at term-equivalent age. Results: A total of 335 infants were screened, 94 of which (preterm: n = 72; term: n = 22) were included. Higher sFlt-1/PlGF ratios were significantly correlated with lower fat-free mass (FFM) z-scores (rs = −0.408; p = 0.004), but not with fat mass (FM) z-scores (p = 0.21), weight (p = 0.19), length (p = 0.31), or head circumference z-scores (p = 0.32) in preterm infants. In a linear regression model adjusted for potential neonatal confounders, higher sFlt-1/PlGF ratios were independently and significantly associated with lower FFM in preterm infants (median: −0.10, 95% CI: −0.2, 0.00; p = 0.036). In term infants, sFlt-1/PLGF ratios were not significantly correlated with FFM (p = 0.86), FM z-scores (p = 0.41), weight (p = 0.10), length (p = 0.12), or head circumference z-scores (p = 0.2). Conclusions: These findings suggest that the sFlt-1/PLGF ratio is not only a well-established marker of HDP severity during pregnancy but may also be associated with adverse effects on body composition in preterm infants, particularly in fat-free mass (FFM). Full article

Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality worldwide. This significant burden necessitates effective early identification of pregnancies at high-risk for preeclampsia. Accurate prediction is essential in order to develop and optimize preventive strategies. The evolution of preeclampsia screening has progressed from a traditional checklist-based approach to individualized, multivariable models. The first-trimester triple test, which was developed by the Fetal Medicine Foundation (FMF), represents this advancement. It utilizes Bayes’ theorem to calculate patient-specific risks by integrating maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor. This model, called “first trimester FMF triple test”, has undergone successful internal and external validation for the prediction of preterm preeclampsia. To ensure the reliability of biomarker measurements and achieve an optimal screening performance, it is essential to implement standardized measurement protocols and rigorous quality control processes in biomarker testing. The triple test could also be utilized in the 2nd and 3rd trimester, and the addition of biomarkers such as soluble fms-like tyrosine kinase-1 further improves risk stratification assessment and continued surveillance of high-risk pregnancies. Full article

Background/Objectives: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is an established biomarker in the diagnosis of preeclampsia; however, its significance outside overt hypertensive disorders of pregnancy remains unclear. Emerging evidence suggests that angiogenic imbalance may reflect subclinical placental dysfunction even in otherwise low-risk pregnancies. To investigate associations between the sFlt-1/PlGF ratio and maternal and neonatal outcomes in a low-risk term obstetric population, beyond established diagnostic cut-offs. Methods: This prospective cohort study included 87 women with singleton term pregnancies. Serum sFlt-1 and PlGF concentrations were measured at hospital admission before delivery, and the sFlt-1/PlGF ratio was calculated. The primary outcome was estimated blood loss at delivery. Secondary maternal outcomes included postpartum hemoglobin decline, uterine atony, and fibrinogen concentration. Neonatal outcomes included birthweight, umbilical artery pH, and bilirubin concentration. Multivariable regression models were used to evaluate associations between the ln-transformed sFlt-1/PlGF ratio and outcomes after adjustment for prespecified maternal and obstetric covariates. Results: Each doubling of the sFlt-1/PlGF ratio was associated with greater estimated peripartum blood loss (+78.0 mL, 95% CI 42.1–113.9; p < 0.001), a larger postpartum hemoglobin decline (+0.078 g/dL, 95% CI 0.008–0.148; p = 0.030), lower fibrinogen concentration (−20.7 mg/dL, 95% CI −30.5 to −10.9; p < 0.001), and lower neonatal birthweight (−64.6 g, 95% CI −102.0 to −27.2; p = 0.001). No significant associations were observed for uterine atony, premature rupture of membranes, or umbilical artery pulsatility index above the 75th centile. Conclusions: In low-risk term pregnancies, higher sFlt-1/PlGF ratios were associated with greater estimated peripartum blood loss, lower fibrinogen concentrations, and lower neonatal birthweight. These findings support the hypothesis that variation in angiogenic balance may reflect subclinical placental dysfunction even in apparently uncomplicated pregnancies. Further prospective studies are needed to validate these exploratory observations and determine their clinical relevance. Full article

Preeclampsia is a pregnancy-specific multisystem disorder and a major cause of maternal and perinatal morbidity and mortality worldwide. This narrative review summarizes current evidence on the principal risk factors and pathophysiological mechanisms involved in its development. The disease is best explained by the two-stage model: in stage 1, inadequate trophoblast invasion and incomplete spiral artery remodeling lead to placental hypoperfusion, hypoxia, and oxidative stress; in stage 2, the hypoxic placenta releases anti-angiogenic and pro-inflammatory factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which trigger systemic endothelial dysfunction and the maternal clinical syndrome. The review highlights the central role of angiogenic imbalance, immune dysregulation, and chronic inflammation in disease progression. Particular emphasis is placed on maternal risk factors such as primiparity, advanced maternal age, obesity, diabetes mellitus, chronic hypertension, multiple pregnancy, prior preeclampsia, genetic susceptibility, and epigenetic regulation. We also emphasize the contribution of microRNAs in relation to placental hypoxia, trophoblast invasion, angiogenesis, endothelial injury and microchimerism to the development of preeclampsia. The review also examines the role of T helper 1 (Th1)/Th2/Th17/regulatory T cells (Treg) imbalance and uterine natural killer cell dysfunction at the maternal–fetal interface. Improved understanding of these interconnected mechanisms may support earlier diagnosis, better risk stratification, and the development of targeted preventive and therapeutic strategies. Full article

Pre-eclampsia and foetal growth restriction (FGR) are major pregnancy complications primarily driven by placental dysfunction, and remain leading causes of maternal and perinatal morbidity. Ultrasound imaging, Doppler studies, and angiogenic biomarkers like placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) constitute the main diagnostic modalities; however, these predominantly reflect established disease rather than early molecular disturbances underlying placentation. The identification of biomarkers directly associated with trophoblast signalling pathways has the potential to improve early risk stratification and enable mechanistic classifications. Kisspeptin signalling via its receptor (KISS1R) regulates trophoblast invasion, extracellular matrix remodelling, ERK1/2 activation, and angiogenic balance, thereby modulating spiral artery transformation. Kisspeptin-10 (KP-10), the minimal bioactive fragment of KISS1, is highly expressed in placental syncytiotrophoblasts and exerts its effects through the G-protein-coupled receptor KISS1R. Core features of early-onset FGR and pre-eclampsia (PE)—including defective placentation, maternal vascular malperfusion, and angiogenic imbalance—have been linked to dysregulation of this pathway. During normal gestation, maternal circulating kisspeptin concentrations rise exponentially. In contrast, pregnancies subsequently complicated by FGR or PE, particularly in the early gestation, are associated with reduced levels. However, the comparability of existing studies and their translational applicability are limited by a substantial methodological heterogeneity, including assay variability, gestational age dependence, and inadequate adjustment for maternal confounders. These limitations hinder robust conclusions regarding the role of kisspeptin in placental pathology. This review critically integrates molecular, pathophysiological, and clinical evidence relating to the role of KP-10 in placental dysfunction. The key question is whether KP-10 represents a mechanistic biomarker of trophoblast signalling dysfunction or merely a secondary marker of reduced placental mass; resolving this distinction is essential. Full article

Offspring of preeclamptic (PE) mothers are at increased risk of end-organ damage. Given the widespread use of NSAIDs during pregnancy and their reported ability to mitigate organ damage in PE mothers, this study examined whether prenatal naproxen modifies PE-induced lung injury in male and female offspring. PE was induced by orally administered L-nitro-arginine-methyl ester (L-NAME, 50 mg/kg/day for 7 days) to mothers prior to labor, and lung tissues were excised from 3-month-old offspring. Histopathology revealed increased interstitial inflammation and fibrosis in PE versus non-PE offspring lungs. This was more prominent in male than in female PE offspring and was coupled with more pulmonary expression of Axl tyrosine kinase receptor and downstream interleukin-1α (IL-1α) and antiangiogenic Fms-Like Tyrosine Kinase-1(sFlt1) effectors. These sex-related defects disappeared in offspring of PE dams treated prenatally with naproxen (1 mg/kg/day for 7 days). Further, PE offspring exhibited elevations in other inflammatory cytokines, IL-2 and TNFα, and apoptotic markers, caspase-3 and caspase-cleaved cytokeratin 18 (M-30) and total soluble cytokeratin 18 (M-65). The latter effects were evenly seen in both sexes and similarly offset by naproxen. These findings implicate Axl/IL-1α/sFlt1 signaling in the greater lung injury in male PE offspring and suggest a protective effect of gestational naproxen therapy. Full article

Preeclampsia is a hypertensive disorder of pregnancy associated with elevated levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and reduced nitric oxide (NO) bioavailability. Esomeprazole (ESO), a proton pump inhibitor (PPI) considered safe during pregnancy, has been proposed to reduce sFlt-1 levels in vitro. This study evaluated the effects of ESO in pregnant rats subjected to reduced uterine perfusion pressure (RUPP), a well-established model of preeclampsia. Pregnant rats received saline (Preg) or ESO (Preg+ESO), while RUPP-operated rats received saline (RUPP) or ESO (RUPP+ESO). At gestational day 21, maternal blood pressure was elevated in the Preg+ESO, RUPP, and RUPP+ESO groups compared with Preg, and ESO did not attenuate RUPP-induced hypertension. Fetal and placental weights were reduced in the RUPP group, whereas ESO increased placental weight in Preg+ESO and RUPP+ESO groups. Gastric pH was elevated by ESO, confirming reduced gastric acidity. Plasma sFlt-1 levels were increased in RUPP and significantly reduced by ESO in RUPP+ESO rats. NO metabolites (NOx) were decreased in RUPP but were unaffected by treatment. Endothelium-dependent relaxation was impaired in the RUPP and RUPP+ESO groups. In conclusion, ESO did not prevent hypertension or endothelial dysfunction, but reduced circulating sFlt-1, suggesting a partial modulatory effect on angiogenic imbalance in experimental preeclampsia. Full article

Preeclampsia involves an angiogenic imbalance, but circulating vascular endothelial growth factor A (VEGF A) remains inconsistently described, particularly in relation to maternal adiposity. We studied 90 second-trimester pregnancies, 30 uncomplicated and 60 with preeclampsia, recording maternal body mass index (BMI) and gestational age at sampling. Serum soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), and VEGF A were measured by enzyme-linked immunosorbent assay (ELISA), and the sFlt1-to-PlGF ratio was calculated. Preeclampsia was associated with higher pre-pregnancy and pregnancy BMI, lower PlGF, and an approximately threefold higher sFlt1-to-PlGF ratio, while sFlt1 alone was only borderline higher. VEGF A was elevated in preeclampsia and rose across higher sFlt1-to-PlGF ratio categories, supporting the interpretation of VEGF A within the integrated sFlt1,PlGF axis rather than as an isolated signal. Full article

Background: Preeclampsia is a major cause of maternal and perinatal morbidity, characterized by placental dysfunction and angiogenic imbalance. The soluble fms-like tyrosine kinase-1-to-placental growth factor (sFlt-1/PlGF) ratio has emerged as a promising biomarker for preeclampsia; however, its prognostic value for maternal and neonatal outcomes remains incompletely defined. Methods: This retrospective cohort study included 320 pregnant women, of whom 68 were diagnosed with preeclampsia, and 252 served as non-preeclamptic controls. Maternal serum sFlt-1 and PlGF levels were measured after 20 weeks of gestation at the time of clinical evaluation for suspected hypertensive disorders of pregnancy. Group comparisons, effect size analysis, receiver operating characteristic (ROC) curve analysis, and multivariable regression models were used to assess diagnostic performance and associations with maternal and neonatal outcomes. Results: The sFlt-1/PlGF ratio was significantly higher in women with preeclampsia compared with non-preeclamptic pregnancies (58.5 ± 17.3 vs. 34.6 ± 19.0; p < 0.001; Cohen’s d = 1.31). ROC analysis demonstrated good discriminative ability for preeclampsia (AUC = 0.81, 95% CI: 0.75–0.87), with a high negative predictive value. Increasing sFlt-1/PlGF values were independently associated with earlier gestational age at delivery, lower birth weight, reduced Apgar (Appearance, Pulse, Grimace, Activity, and Respiration) score, and a higher likelihood of neonatal intensive care unit admission. Conclusions: The sFlt-1/PlGF ratio is a robust biomarker for preeclampsia, providing both diagnostic discrimination and prognostic information regarding maternal and neonatal outcomes. Its integration into clinical practice may support clinical risk awareness when interpreted in the context of standard clinical evaluation and support informed decision-making in pregnancies with suspected or confirmed preeclampsia. Full article

Normal pregnancy is associated with uterine and vascular remodeling by matrix metalloproteinases (MMPs) to facilitate placental blood flow and uterine expansion for the growing fetus. Increases in MMP-2 and MMP-9 in response to estrogen and progesterone promote placentation, uteroplacental vascularization and fetal growth during healthy pregnancy, but are altered in preeclampsia (PE). PE is characterized by hypertension in pregnancy (HTN-Preg) and fetal growth restriction (FGR). Predisposing genetic, demographic and environmental factors alter uteroplacental MMPs, immune response and integrins leading to apoptosis of invasive trophoblasts, inadequate spiral arteries remodeling, and reduced uteroplacental perfusion pressure (RUPP). Ensuing placental ischemia causes imbalance between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and pro-angiogenic placental growth factor (PlGF) and promotes the release of tumor necrosis factor-α (TNF-α), hypoxia-inducible factor, reactive oxygen species, and angiotensin AT₁ receptor agonistic autoantibodies. Systemically, these bioactive factors target vascular endothelial cells, smooth muscle cells, and extracellular matrix, causing endothelial dysfunction, vasoconstriction, inadequate vascular remodeling, and HTN-Preg, while locally they diminish uteroplacental remodeling and cause FGR. In support, animal models of HTN-Preg induced by RUPP or infusion of sFlt-1 or TNF-α show decreases in vascular MMP-2, MMP-9 and vasodilation, increases in MMP-1, MMP-7 and vasoconstriction, collagen accumulation, and arterial stiffness. Also, decreases in uterine MMP-2 and MMP-9 could impede uterine expansion and lead to preterm birth. Conversely, PlGF and TNF-α antagonist reversed MMPs imbalance and collagen accumulation, and improved vascular function, blood pressure, and pup weight in HTN-Preg models. Persistent postpartum changes in MMPs could affect maternal hemorrhage, future pregnancies, and HTN, and cause fetal programming of cardiovascular and metabolic diseases. Understanding the aberrant uteroplacental and vascular signaling and remodeling by MMPs could help design new biomarkers and remedies for PE. Targeting bioactive factors and rectifying MMP imbalance could improve vascular and uteroplacental remodeling, and manage HTN-Preg, FGR and PE. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Preeclampsia (PE) affects 2–8% of pregnancies, yet it lacks curative treatment options. Oxidative stress caused by the release of reactive oxygen and nitrogen species (ROS/RNS) in the placenta is common in abnormal placental development. It can cause downstream signaling and the formation of anti-angiogenic factors, e.g., soluble fms-like tyrosine kinase 1 (sFLT-1), leading to symptoms of PE, such as hypertension, proteinuria, and, in severe cases, eclampsia. Mitochondria-targeted antioxidants were developed to reduce oxidative stress and alleviate PE symptoms. Ten organofluorine diaryl hydrazones were designed as potential antioxidants, synthesized, and tested for their activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and oxygen radical absorbance capacity (ORAC) assays. Compounds 2, 3, 5, and 6 showed excellent antioxidant capacity in all three assays and were tested in an in vitro human trophoblast cell culture system mimicking PE in which the cells were exposed to oxidative stress inducing the release of sFLT-1. The anti-angiogenic factor sFLT-1 was greatly reduced in cells treated with antioxidants. Compounds 5 and 6 were more effective in preventing sFLT-1 release than 2 and 3. Density functional theory calculations of the electronic structures of compounds 2, 5, and 6 were conducted at the M06-2X/6-311G+(d,p) level to further understand the reactivity profile of these molecules. The electron density of delocalized bonds (EDDB(r)) was calculated to analyze the effect of delocalization on radical stabilization. Full article

Background: The placenta plays a fundamental role in supporting fetal development, with angiogenesis being crucial for establishing an efficient maternal–fetal interface. Epigenetic mechanisms, particularly DNA methylation, can regulate the expression of angiogenesis-related genes and may be influenced by Assisted Reproductive Technology (ART), including In Vitro Fertilization (IVF) with fresh or frozen-thawed embryo transfer (ET and FET, respectively) and egg donation (ED), all potentially affecting placental vascular development and pregnancy outcomes. The present study compared global DNA methylation levels and the expression of Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PlGF), and Soluble Fms-Like Tyrosine kinase-1 (sFlt-1) in placentae from physiological pregnancies obtained using ART versus those spontaneously conceived. Methods: Placental biopsies were collected from 98 physiological singleton term pregnancies (CTRL n = 29, ET n = 23, FET n = 25, ED n = 21). Global DNA methylation (5-mC) was quantified by ELISA Easy Kit; VEGF, PlGF, sFlt-1 mRNA and protein levels were assessed by Real-Time PCR and ELISA, respectively. Results: Global DNA methylation was significantly increased in FET and ED placentae compared with CTRL and ET. PlGF mRNA expression was upregulated in all ART groups, although protein levels were elevated only in ED placentae compared to CTRL and ET groups. VEGF mRNA was increased in FET placentae compared to CTRL, while protein levels showed a non-significant upward trend across ART groups. No differences in sFlt-1 expression were observed. Clinically, ART pregnancies were associated with significantly lower birth weight compared to CTRL, though values remained within the physiological range, and placental efficiency was preserved. Conclusions: Hypermethylation in FET and ED placentae may act as an epigenetic “buffer,” stabilizing vulnerable genomic regions and supporting the expression of pro-angiogenic factors. This adaptive mechanism likely helps to preserve placental function and fetal viability despite ART-related stressors, thereby mitigating the potential impact on birth weight. Full article