Placental Syndromes Research Articles

P182 AORTIC VASCULAR BIOMARKERS FOR THE EARLY DETECTION OF PLACENTAL SYNDROMES DURING PREGNANCY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: Placental syndromes (PS) cause over 14 million complications and the death of more than 350,000 women each year. Women with preeclampsia (PE) or gestational hypertension (GH) typically exhibit late gestational acute brachial hypertension, making early intervention difficult. Non-invasive aortic waveform assessments provide nuanced insight to global cardiovascular function. Our objective is to delineate cardiovascular differences between complicated and normotensive pregnancies (NP), to identify early vascular markers of at-risk women. Methods: A systematic search (March 2024) for studies reporting both NP and PS pregnancies was performed across five databases: PubMed; Medline; CINAHL Complete; Web of Science; and Scopus. Inclusion criteria required reporting before, during (trimester: T1; T2; T3), or after pregnancy (< 1 year post-delivery) of at least one of the following vascular biomarkers from aortic pulse pressure waveform: aortic systolic blood pressure (aSBP); aortic pulse pressure (aPP); augmentation index normalised to a heart rate of 75 bpm (AIx@75); or arterial stiffness measured by carotid femoral pulse wave velocity (cfPWV). A meta-analysis of continuous random-effects model calculated Hedges’ g with 95% confidence intervals. Results: The systematic search yielded 19 studies. Analysis depicted PS having significantly higher aggregated measures than NP throughout pregnancy (p <0.001) and a stronger effect size of AIx@75, aSBP, cfPWV in each trimester [T1, Hedges g 1.4(CI .64 - 2.0); T2, 1.1(CI .64 - 1.5); T3, 3.4(CI 2.1 – 4.6) p<0.001]. Overall, cfPWV had the highest effect size particularly during T1 and T3 [T1, 2.8(CI 2.5 – 3.1); T2, 1.7(CI 1.2 – 2.1); T3, 5.3(CI 4.6 – 5.9)]. Low aPP reporting allowed only analysis of T3 which showed similar effect sizes to other markers [3.14(CI 1.23 – 5.05)]. Conclusions: Early indication of PS was quantifiable from vascular biomarkers, along with each trimester of pregnancy being elevated compared to NP. Pulse wave analysis and arterial stiffness assessment could enhance risk assessment from as early as the first trimester, improving and informing prenatal care.

Endogenous retrovirus HERVH-derived lncRNA UCA1 controls human trophoblast development

Endogenous retroviruses (ERVs) are frequently reactivated in mammalian placenta. It has been proposed that ERVs contribute to shaping the gene regulatory network of mammalian trophoblasts, dominantly acting as species- and placental-specific enhancers. However, whether and how ERVs control human trophoblast development through alternative pathways remains poorly understood. Besides the well-recognized function of human endogenous retrovirus-H (HERVH) in maintaining pluripotency of early human epiblast, here we present a unique role of HERVH on trophoblast lineage development. We found that the LTR7C/HERVH subfamily exhibits an accessible chromatin state in the human trophoblast lineage. Particularly, the LTR7C/HERVH-derived Urothelial Cancer Associated 1 (UCA1), a primate-specific long non-coding RNA (lncRNA), is transcribed in human trophoblasts and promotes the proliferation of human trophoblast stem cells (hTSCs), whereas its ectopic expression compromises human trophoblast syncytialization coinciding with increased interferon signaling pathway. Importantly, UCA1 upregulation is detectable in placental samples from early-onset preeclampsia (EO-PE) patients and the transcriptome of EO-PE placenta exhibits considerable similarities to that of the syncytiotrophoblasts differentiated from UCA1-overexpressing hTSCs, supporting up-regulated UCA1 as a potential biomarker of this disease. Altogether, our data shed light on the versatile regulatory role of HERVH in early human development and provide a unique mechanism whereby ERVs exert a function in human placentation and placental syndromes.

Investigating the molecular mechanism of traditional Chinese medicine for the treatment of placental syndromes by influencing inflammatory cytokines using the Mendelian randomization and molecular docking technology.

Placental syndromes, which include pregnancy loss, preterm birth, gestational diabetes mellitus (GDM), and hypertensive disorders in pregnancy (HDP), have a strong association with disorder inflammatory reactions. Nonetheless, the exact causal relationship has not been established. This study aims to investigate the causal relationship between placental syndromes and inflammatory cytokines utilizing Mendelian randomization (MR). Additionally, we examined the interaction between small molecular compounds derived from traditional Chinese medicine and inflammatory cytokines using molecular docking method. After obtaining the data of inflammatory cytokines and placental syndromes, as well as establishing single nucleotide polymorphisms (SNPs), we employed the inverse variance weighted (IVW) method to assess the causal relationship. We also accessed the heterogeneity and the horizontal pleiotropy of these data. The "ClusterProfiler" R package was utilized for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term analyses. The protein-protein interaction (PPI) network was constructed using STRING database. AutoDock Vina software was used for molecular docking, and Discovery Studio 2019 was used for visualization purposes. We found that the growth regulated oncogene A (GROA) and interleukin-9 (IL-9) were associated with the development of pregnancy hypertension, whereas interleukin-10 (IL-10) and hepatocyte growth factor (HGF) were linked to the occurrence of preeclampsia. Moreover, there were correlations observed between interleukin-18 (IL-18), IL-10, macrophage colony-stimulating factor (MCSF), and platelet-derived growth factor BB (PDGFbb) in cases of chronic hypertension combined with pregnancy (CHP). Additionally, macrophage migration inhibitory factor (MIF) exhibited a connection with GDM, and TNF related apoptosis inducing ligand (TRAIL) demonstrated a causal relationship with preterm birth. It is plausible to suggest that interleukin-1β (IL-1β) might contribute to the promotion of pregnancy loss. All of the binding free energy values of small molecular compounds with inflammatory cytokines were below -5.0 kcal/mol. Furthermore, all of the RMSD values were less than 2. GROA, IL-1β, IL-9, IL-10, IL-18, MIF, MCSF, HGF, PDGFbb and TRAIL were found to be causally associated with placental syndromes. Molecular docking analysis revealed that small molecular compounds, such as puerarin, magnolol, atractylenolide I, paeoniflorin, tumulosic acid and wogonin, are closely bound to these inflammatory cytokines.

Defining trophoblast injury patterns in the transcriptomes of dysfunctional placentas

Trophoblast injury is central to clinically relevant placenta dysfunction. We hypothesized that the mRNA of primary human trophoblasts, exposed to distinct injuries in vitro, capture transcriptome patterns of placental biopsies obtained from common obstetrical syndromes. We deployed a CIBERSORTx deconvolution method to correlate trophoblastic RNAseq-based expression matrices with the transcriptome of omics-defined placental dysfunction patterns in vivo. We found distinct trophoblast injury patterns in placental biopsies from women with fetal growth restriction and a hypertensive disorder, or in biopsies clustered by their omics analysis. Our RNAseq data are useful for defining the contribution of trophoblast injuries to placental dysfunction syndromes.

Reduced Proliferative Potential with Conserved Stem/Stromal Phenotype of Human Umbilical Cord Mesenchymal Stem Cells in Placental Syndromes: A Prospective Cohort Study

Reduced Proliferative Potential with Conserved Stem/Stromal Phenotype of Human Umbilical Cord Mesenchymal Stem Cells in Placental Syndromes: A Prospective Cohort Study

From Molecules to Imaging: Assessment of Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes.

Placental hypoxia poses significant risks to both the developing fetus and the mother during pregnancy, underscoring the importance of early detection and monitoring. Effectively identifying placental hypoxia and evaluating the deterioration in placental function requires reliable biomarkers. Molecular biomarkers in placental tissue can only be determined post-delivery and while maternal blood biomarkers can be measured over time, they can merely serve as proxies for placental function. Therefore, there is an increasing demand for non-invasive imaging techniques capable of directly assessing the placental condition over time. Recent advancements in imaging technologies, including photoacoustic and magnetic resonance imaging, offer promising tools for detecting and monitoring placental hypoxia. Integrating molecular and imaging biomarkers may revolutionize the detection and monitoring of placental hypoxia, improving pregnancy outcomes and reducing long-term health complications. This review describes current research on molecular and imaging biomarkers of placental hypoxia both in human and animal studies and aims to explore the benefits of an integrated approach throughout gestation.

Nanomedicines: An approach to treat placental insufficiency and the current challenges.

Preeclampsia and fetal growth restriction are common pregnancy complications that significantly impact perinatal health and offspring development later in life. The origin of these complex syndromes overlap in placental insufficiency. Progress in developing treatments for maternal, placental or fetal health is mainly limited by the risk of maternal and fetal toxicity. Nanomedicines are a promising approach to safely treat pregnancy complications since they can regulate drug interaction with the placenta to enhance efficacy of the treatment while minimizing exposure of the fetus. This narrative review discusses the current developments and challenges of nanomedicines during pregnancy with a focus on preclinical models of placenta insufficiency syndromes. Firstly, we outline the safety requirements and potential therapeutic maternal and placental targets. Secondly, we review the prenatal therapeutic effects of the nanomedicines that have been tested in experimental models of placental insufficiency syndromes. The majority of liposomes and polymeric drug delivery system show promising results regarding the prevention of trans-placental passage nanomedicines in uncomplicated and complicated pregnancies. The others two studied classes, quantum dots and silicon nanoparticles, have been investigated to a limited extent in placental insufficiency syndromes. Characteristics of the nanoparticles such as charge, size, and timing of administration have been shown to influence the trans-placental passage. The few available preclinical therapeutic studies on placental insufficiency syndromes predominantly show beneficial effects of nanomedicines on both maternal and fetal health, but demonstrate contradicting results on placental health. Interpretation of results in this field is complicated by the fact that results are influenced by the choice of animal species and model, gestational age, placental maturity and integrity, and nanoparticle administration route. Nanomedicines form a promising therapeutic approach during (complicated) pregnancies mainly by reducing fetal toxicity and regulating drug interaction with the placenta. Different nanomedicines have been proven to effectively prevent trans-placental passage of encapsulated agents. This can be expected to dramatically reduce risks for fetal adverse effects. Furthermore, a number of these nanomedicines positively impacted maternal and fetal health in animal models for placental insufficiency. Demonstrating that effective drug concentrations can be reached in the target tissue. While these first animal studies are encouraging, more research is needed to better understand the influence of the pathophysiology of this multi-factorial disease before implementation in clinical practice can be considered. Therefore, extensive evaluation of safety and efficacy of these targeted nanoparticles is needed within multiple animal, in vitro, and/or ex vivo models. This may be complemented by diagnostic tools to assess the disease status to identify the best time to initiate treatment. Together these investigations should contribute to building confidence in the safety of nanomedicines for treating mother and child, as safety has, understandably, the highest priority in this sensitive patient groups.

Tek kat ve çift kat onarımın rezidüel miyometriyal kalınlık, istmosel oluşumu ve jinekolojik bozukluklar üzerine etkisi: Prospektif Randomize Kontrollü Bir Çalışma.

Abstract:
 Physicians are making great efforts to decrease the long-term complications of the cesarean section such as placental adherent syndromes, uterine scar pregnancies, uterine rupture, abnormal menstrual bleeding, or isthmocele. There is a controversy about the closure technique of the cesarean incision. The purpose of that study was to compare the impact of single layer versus double-layer closure of the hysterotomy incision on the residual myometrial thickness, isthmocele, menstrual disorders, dysmenorrhea, and dyspareunia.
 Material and Method
 A prospective randomized cohort study has been performed in a tertiary center named Bursa Yuksek İhtisas Training Research Hospital between July – October 2021. Patients were randomly assigned to each procedure (1:1) to the Single Layer Locked Continuous group and Double-layer Continuous un-locked group as uterine closure technique. Patients were examined via transvaginal ultrasound to evaluate the isthmocele occurrence, residual myometrium thickness, and inquired about menstrual properties, dysmenorrhea, and dyspareunia. Patients were also divided into groups via underwent first cesarean and more than one cesarean. 
 Results:
 The numbers of the women whose hysterotomy incision was closed by single-layer locked continuous( SLLC) technique and double-layer un-locked continuous(DLUC) technique 68 and 71 respectively. There was no statistically significant difference in terms of demographic variables, obstetric history, post-operative complications, neonatal outcomes. The comparison of these groups revealed that there was no significant difference in terms of post-menstrual bleeding, heavy menstrual bleeding, post-coital bleeding, dysmenorrhea, dyspareunia. The incisional residual myometrial thickness was higher in the DLUC group with a p-value of 0,007. Six patients in SLLC and 5 patients in the DLUC group have detected isthmocele (p: 0,941). 
 Patients have also been categorized as women who undergone their first cesarean section (SLLC n: 33 versus DLUC, n:33) and more than one cesarean section (SLLC n: 35 versus DLUC, n:38). Comparing the patients in these subgroups also did not differ significantly in terms of isthmocele occurrence, menstrual disorders, or residual myometrial thickness. 
 Conclusion:
 No significant difference had occurred in terms of isthmocele incidence, or menstrual disorders comparing the single layer versus double-layer closure. However, women whose hysterotomy insicions were closed with double-layer un-locked continuous technique have a thicker resudial myometrium than single layer closure group especially women who underwent repeated cesarean.

Alterations in maternal sFlt-1 and PlGF: Time to labor onset in term-/late-term pregnancies with and without placental dysfunction.

To investigate the placenta-associated biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) longitudinally in late third trimester extending to late-term pregnancies, and their correlation with time to labor onset in pregnancies with and without placental syndromes (ie preeclampsia and/or fetal growth restriction). Also, to compare whether time to labor onset after induction differ between these groups. Pregnant women (n=338, of which 75 had a placental syndrome) with serial blood samples from gestational week ≥37 until labor onset were included. Maternal serum PlGF and sFlt-1 concentrations were analyzed by immunoassay postpartum. Rate of alteration in sFlt-1, PlGF and the sFlt-1/PlGF ratio prior to labor onset. Secondary outcome was rates of delivery within 48h of labor induction. In placental syndrome pregnancies, sFlt-1 and sFlt-1/PlGF ratio increased more rapidly between the two last samples prior to labor onset compared to uncomplicated pregnancies (both p<0.01), but there was no difference in the PlGF decrease (p=0.513). Time to labor onset was significantly shorter in pregnancies with placental syndromes compared to those without (p=0.001). In the induced deliveries, there was no difference in delivery within 48h between the two groups. An increase in sFlt-1 and sFlt-1/PlGF ratio at term prior to labor onset is more rapid in pregnancies with placental syndromes. This more rapid antiangiogenic shift might indicate a pregnancy more prone to acute placental failure and more inflammatory prepared for labor onset. Effect of labor induction was not impacted by placental dysfunction.

Placental Syndromes-A New Paradigm in Perinatology.

Placental syndromes include pregnancy loss, fetal growth restriction, preeclampsia, preterm delivery, premature rupture of membranes, placental abruption and intrauterine fetal demise. This paper discusses the common etiopathogenesis of those syndromes and the role of angiogenic biomarkers in their development. Pregnancy implantation, placental development and maternal adaptation are complex processes in which fetal and maternal cells interact. The syncytiotrophoblast, trophoblast, uterine natural killer cells and regulatory T cells interfere and interact in all the above-mentioned processes. The proper angioneogenesis and vasculogenesis of the placenta, as well as maternal circulatory adaptation, are dependent on angiogenic factor expression. Insufficient maternal immunotolerance, dysregulation in uterine natural killer or regulatory T cell function, syncytiotrophoblast and trophoblast ischemia and hypoxia or impaired balance in angiogenic factors are all related to the occurrence of placental syndromes. Differences in the time of impairment onset and its intensity and correlation with other dysfunctions result in the development of a specific syndrome. The clinical manifestations in the form of a combination of specific symptoms determine the diagnosis. However, they are just symptoms of an underlying complex trophoblast disorder.

Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.

THE CASE OF PREGNANCY IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Patients with systemic lupus erythematosus (SLE) have such clinical manifestations as multiple thrombosis, PE, CNS diseases, livedo reticularis, labile hypertension, and habitual miscarriage. SLE affects people of all races, men and women, but in the latter it is dominant and especially often develops in women of reproductive age. Currently, it is generally recognized that such gestational complications as habitual abortion, preeclampsia and eclampsia, premature placental abruption, DIC and HELLP syndromes, thrombosis, fetal growth retardation, stillbirth, are associated with autoimmune diseases in the mother. The mechanism by which SLE aggravates the course of pregnancy and worsens its outcomes for the mother, fetus, and newborn remains undeciphered.

“The First Thousand Days” Define a Fetal/Neonatal Neurology Program

Gene–environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.

Galectin Family in Placental Insufficiency Syndromes

Galectin Family in Placental Insufficiency Syndromes

Use of a human embryonic stem cell model to discover GABRP, WFDC2, VTCN1 and ACTC1 as markers of early first trimester human trophoblast.

Human placental development during early pregnancy is poorly understood. Many conceptuses are lost at this stage. It is thought that preeclampsia, intrauterine growth restriction and other placental syndromes that manifest later in pregnancy may originate early in placentation. Thus, there is a need for models of early human placental development. Treating human embryonic stem cells (hESCs) with BMP4 (bone morphogenic protein 4) plus A83-01 (ACTIVIN/NODAL signaling inhibitor) and PD173074 (fibroblast growth factor 2 or FGF2 signaling inhibitor) (BAP conditions) induces differentiation to the trophoblast lineage (hESCBAP), but it is not clear which stage of trophoblast differentiation these cells resemble. Here, comparison of the hESCBAP transcriptome to those of trophoblasts from human blastocysts, trophoblast stem cells and placentas collected in the first-third trimester of pregnancy by principal component analysis suggests that hESC after 8 days BAP treatment most resemble first trimester syncytiotrophoblasts. To further test this hypothesis, transcripts were identified that are expressed in hESCBAP but not in cultures of trophoblasts isolated from term placentas. Proteins encoded by four genes, GABRP (gamma-aminobutyric acid type A receptor subunit Pi), WFDC2 (WAP four-disulfide core domain 2), VTCN1 (V-set domain containing T-cell activation inhibitor 1) and ACTC1 (actin alpha cardiac muscle 1), immunolocalized to placentas at 4-9 weeks gestation, and their expression declined with gestational age (R2 = 0.61-0.83). None are present at term. Expression was largely localized to syncytiotrophoblast of both hESCBAP cells and placental material from early pregnancy. WFDC2, VTCN1 and ACTC1 have not previously been described in placenta. These results support the hypothesis that hESCBAP represent human trophoblast analogous to that of early first trimester and are a tool for discovery of factors important to this stage of placentation.

Predictive possibility of the transverse cerebellar diameter to abdominal circumference ratio for small-for-gestational-age fetus suspected as a cause of maternal placental syndromes: a retrospective cohort study

ABSTRACT Objective To examine whether fetal transverse cerebellar diameter (TCD) to abdominal circumference (AC) ratio can predict small-for-gestational age suspected as a cause of maternal placental syndromes (SGA-MPS). Methods We evaluated 473 women who underwent ultrasound examinations at 24–28 weeks of gestation. A receiver operating characteristic curve was used to determine the TCD/AC ratio thresholds to predict SGA-MPS. We used multivariable logistic regression analysis to examine the association. Results TCD/AC ratio>14.37 was associated with SGA-MPS. Conclusions Accurate risk stratification using the TCD/AC ratio could assist in managing patients with small-for-gestational-age fetuses at risk of developing MPS-associated adverse outcomes.

Fetal microchimerism and implications for maternal health.

This review paper outlines the definition, pathophysiology, and potential maternal health consequences of cellular fetal microchimerism, the maternal acquisition of intact cells of fetal origin during pregnancy. Increased rates and amounts of cellular fetal microchimerism are associated with several placental syndromes, including preeclampsia and fetal growth restriction. The discovery of cellular fetal microchimerism and methods of detection are briefly outlined, and we present the mechanisms hypothesized to govern pregnancy-related and long-term maternal health effects of cellular fetal microchimerism. Specifically, we discuss the potential implications of cellular fetal microchimerism in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cellular fetal microchimerism represents a novel area of research on maternal and transgenerational health and disease, providing exciting opportunities for developing new disease biomarkers and precision medicine with targeted prophylaxis against long-term maternal disease.

Third stage of labor placental complications and placenta-associated syndromes

Objective To evaluate the association between third stage placental complications and placental insufficiency associated disorders, also known as, placenta associated syndromes. Study design A population-based retrospective cohort study comparing placental-related perinatal outcomes of parturient with (study group) and without third stage placental complications, defined as a composite of retained placenta, adherent placenta, placenta accrete, need for manual removal of the placenta, postpartum curettage and revision of the uterine cavity. A univariate analysis was followed by a multivariable logistic regression model. Results During the study period, 263,023 deliveries met inclusion criteria, of which, 10,281 (3.9%) experienced placental complications during the third stage of labor. Parturient in the study group had significantly higher rates of placental insufficiency associated disorders which included among others: hypertensive disorders of pregnancy (6.5 versus 5.6%, p < .001), stillbirth (1.9 versus 0.7%, p < .001) and preterm delivery (9.9 versus 7.7%, p < .001). Using a multivariable regression model, while controlling for confounders such as maternal age and induction of labor, third stage placental complications were independently associated with placental insufficiency associated disorders. Conclusion Our findings suggest that placental associated adverse pregnancy outcomes and third stage placental complications may represent different manifestations of a common pathological or inadequate placentation process.

Early-Pregnancy Circulating Antioxidant Capacity and Hemodynamic Adaptation in Recurrent Placental Syndrome: An Exploratory Study

Background/Aims: Placental syndromes (PS) refer to pregnancy complications that include gestational hypertension, (pre)eclampsia, HELLP syndrome, and/or placental insufficiency-induced fetal growth restriction. These disorders are characterized by increased oxidative stress. This study aims to test the hypothesis that the abnormal hemodynamic adaptation to pregnancy, typical for early PS pregnancy, is accompanied by abnormal maternal levels of antioxidants relative to those in normal pregnancy. Methods: Before, and at 12, 16, and 20 weeks pregnancy, we measured trolox equivalent antioxidant capacity (TEAC), uric acid (UA), and TEACC (TEAC corrected for UA) in maternal serum of former PS patients, who either developed recurrent PS (rPS; n = 16) or had a normal next pregnancy (non-rPS; n = 23). Concomitantly, we also measured various hemodynamic variables. Results: rPS differed from non-rPS by higher TEACC levels before pregnancy (178 vs. 152 µM; p = 0.02) and at 20 weeks pregnancy (180 vs. 160 µM; p = 0.04). Only non-rPS responded to pregnancy by significant rises in hemodynamic measures. Conclusion: These data indicate that rPS pregnancies are preceded by an increase in antioxidant capacity, presumably induced by subclinical vascular injury and low-grade chronic inflammation.

Placental Dysfunction As a Key Element in The Pathogenesis of Preeclampsia

Placental pathology is associated with major pregnancy disorders and the concept of the Great Placental Syndromes encompasses disorders of placentation, such as preeclampsia with and without fetal growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and placental abruption. Preeclampsia is divided between the early and late onset variety and placental dysfunction is a central feature in the pathogenesis of both. In the early onset type, syncytiotrophoblastic stress seems to be related to an inherent defect of the trophoblast. Vascular protection of early placental development is replaced by vascular dysfunction. In late onset preeclampsia, maternal factors, such as genotypic predisposition to endothelial disease, and an impairment of antioxidant defence with a limited capacity of the maternal clearing system to cope with the increasing charge of apoptotic cell debris, are at the center of pathogenesis. Syncytiotrophoblastic stress in late pregnancy has been related to molecular senescence and late onset preeclampsia may be viewed as an exaggeration of normal placental ageing.