Placental Maturation Research Articles

Utero-Placental Immune Milieu during Normal and Aglepristone-Induced Parturition in the Dog.

Simple SummaryThe tolerance of the maternal immune system towards the embryo is essential for the success of pregnancy in all mammals. The uterine immunological milieu is modulated in a species-dependent manner, and pro-inflammatory responses are observed in the uterus during parturition in several species. An analogous situation was suggested for the dog. Nevertheless, details regarding immune signaling in the canine utero-placental compartments remain veiled. The present investigation of gene expression and immunolocalization of several immune-related factors revealed moderate utero-placental activity during mid-pregnancy (maintenance period). However, several immune factors were upregulated during parturition, suggesting an increased incidence of cells involved in tissue remodeling and/or immune regulation. The involvement of progesterone in these mechanisms was further assessed by using samples from mid-pregnant dogs treated with the progesterone receptor blocker, aglepristone. Similarities were observed in the expression pattern of several immune factors between natural and induced parturition, supporting the involvement of progesterone signaling in the modulation of the uterine immune milieu. This study provides the basis for further investigations regarding the immune regulation of parturition in the dog. Furthermore, differences observed between natural and induced parturition could be related to different placental maturation and/or functional characteristics of aglepristone, and might be of clinical relevance.Maternal immunotolerance is required for the maintenance of pregnancy, in sharp contrast with the uterine pro-inflammatory activity observed during parturition in several species. Correspondingly, in the dog, increased immune signaling at term has been suggested, but a deeper understanding of the uterine immune milieu is still missing. Thus, the availability of 30 immune-related factors was assessed in utero-placental samples collected during post-implantation (days 18–25 of pregnancy) and mid-gestation (days 35–40) stages, and at the time of prepartum luteolysis. Gene expression and/or protein localization studies were employed. Samples collected from antigestagen (aglepristone)-treated dogs were further analyzed. Progression of pregnancy was associated with the downregulation of IL1β and upregulation of IL10 (p < 0.05) at mid-gestation. When compared with mid-gestation, a higher availability of several factors was observed at term (e.g., CD206, CD4, TLR4). However, in contrast with natural parturition, MHCII, CD25, CCR7, TNFα, IDO1 and AIF1 were upregulated after aglepristone treatment (p < 0.05), but not TNFR1 or CCL13 (p > 0.05). Altogether, these results show an increased immune activity during canine parturition, involving, i.a., M2 macrophages, Treg and Th cells, with strong support for progesterone-mediated immunomodulation. Furthermore, differences between term and induced parturition/abortion could relate to differences in placental maturation towards parturition and/or functional traits of antigestagens.

Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation.

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

Perinatal Outcomes in Premature Placental Calcification and the Association of a Color Doppler Study: Report from a Tertiary Care Hospital in Eastern India.

Introduction: Placental calcification, identified before the 36th week of gestational age, is known as premature placental calcification (PPC). PPC could be a clue for the poor fetal outcome. However, its association with adverse perinatal outcomes is yet to be confirmed. Objective: The primary objective was to determine and compare the perinatal outcomes in pregnancies with and without documented premature placental calcification. Methodology: The present study was a prospective cohort study performed from October 2017 to September 2019. We consecutively enrolled 494 antenatal women who presented to our antenatal OPD after taking consent to participate in our study. Transabdominal sonographies were conducted between 28–36 weeks of gestation to document placental maturity. We compared maternal and fetal outcomes between those who were identified with grade III placental calcification (n = 140) and those without grade III placental calcification (n = 354). Results: The incidence of preeclampsia, at least one abnormal Doppler index, obstetrics cholestasis, placental abruption, and FGR (fetal growth restriction) pregnancies were significantly higher in the group premature placental calcification. We also found a significantly increased incidence of Low APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores, NICU (Neonatal Intensive Care Unit) Admission, Abnormal CTG (cardiotocography), meconium-stained liquor, and low birth weight babies in those with grade III placental calcification. Conclusion: Clinicians should be aware of documenting placental grading while performing ultrasonography during 28 to 36 weeks. Ultrasonographically, the absence of PPC can define a subcategory of low-risk pregnant populations which probably need no referral to specialized centers and can be managed in these settings.

APPLAUSE: Automatic Prediction of PLAcental health via U-net Segmentation and statistical Evaluation.

Artificial-intelligence population-based automated quantification of placental maturation and health from a rapid functional Magnetic Resonance scan. The placenta plays a crucial role for any successful human pregnancy. Deviations from the normal dynamic maturation throughout gestation are closely linked to major pregnancy complications. Antenatal assessment in-vivo using T2* relaxometry has shown great promise to inform management and possible interventions but clinical translation is hampered by time consuming manual segmentation and analysis techniques based on comparison against normative curves over gestation. This study proposes a fully automatic pipeline to predict the biological age and health of the placenta based on a free-breathing rapid (sub-30 second) T2* scan in two steps: Automatic segmentation using a U-Net and a Gaussian process regression model to characterize placental maturation and health. These are trained and evaluated on 108 3T MRI placental data sets, the evaluation included 20 high-risk pregnancies diagnosed with pre-eclampsia and/or fetal growth restriction. An independent cohort imaged at 1.5T is used to assess the generalization of the training and evaluation pipeline. Across low- and high-risk groups, automatic segmentation performs worse than inter-rater performance (mean Dice coefficients of 0.58 and 0.68, respectively) but is sufficient for estimating placental mean T2* (0.986 Pearson Correlation Coefficient). The placental health prediction achieves an excellent ability to differentiate cases of placental insufficiency between 27 and 33 weeks. High abnormality scores correlate with low birth weight, premature birth and histopathological findings. Retrospective application on a different cohort imaged at 1.5T illustrates the ability for direct clinical translation. The presented automatic pipeline facilitates a fast, robust and reliable prediction of placental maturation. It yields human-interpretable and verifiable intermediate results and quantifies uncertainties on the cohort-level and for individual predictions. The proposed machine-learning pipeline runs in close to real-time and, deployed in clinical settings, has the potential to become a cornerstone of diagnosis and intervention of placental insufficiency. APPLAUSE generalizes to an independent cohort imaged at 1.5T, demonstrating robustness to different operational and clinical environments.

Histological criteria of maturity of the uterine-placental area of manure

In order to improve the procedure of morphological diagnosis of the degree of maturity of the uterine-placental area of the placenta, the authors conducted special studies of the structures of the placental bed of the uterus at different stages of gestation during physiological pregnancy and under various pathologies of the mother or placenta. Criteria for maturity of the uterine-placental area of manure in gestational segments 13-27, 28-36 and 37-40 weeks based on the percentage of spiral arteries with complete gestational remodeling of the walls due to the destructive effect of invasive trophoblast and the first parameters of the norm for the number of veins per unit area in the uterine-placental area. To morphologically determine the degree of maturity of the uteroplacental area, a table of the percentage of spiral arteries with complete gestational adjustment and the number of venous vessels per 1 mm2 area of histological section according to gestational age. For morphological diagnosis of the degree of maturity of the placenta at different stages of gestation during physiological pregnancy and under conditions of different pathology of the mother or placenta, it is recommended to conduct a comprehensive morphological assessment of placental structures using maturity criteria of placental chorionic tree and maturity criteria of placental placenta.

Prevention of the fetoplacental complex disorders in women at risk and the risk of preterm birth (Literature review)

The obstetrician-gynaecologist practitioners consider a woman’s health from her reproductive potential support standpoint, and the problem of miscarriage is considered as one of the most important health problems in the world. The difficulty in solving the premature birth problem is the presence of many factors and preconditions that determine the risks of miscarriage. The article provides an overview of current international guidelines for assessing the root causes and preconditions for preterm birth. The problem of preterm birth risks is discussed, taking into account both the socio-economic living conditions of pregnant women and the factors that accompany the formation of the pathogenesis of preterm birth (placental dysfunction). There were examination and evaluation of the clinical significance of the factors that can lead to dysfunction of the fetoplacental complex (partial placental abruption, low placentation, placental dysfunction, premature placental maturation, placental malnutrition/hypertrophy, polyhydramnios/dehydration, placental abruption syndrome and growth retardation syndrome, fetal-placental blood flow, acute/chronic fetal distress). It was noted that hemodynamic disorders in the placenta depend on both the nature and duration of adverse factors. Those factors are pregnancy in unfavourable terms for the birth of children (up to 18 and after 40 years), high frequency of extragenital pathology, complicated reproductive history, genital infectious diseases (chlamydial infections, trichomoniasis, urogenital mycoplasmosis), smoking during pregnancy, the impact of environmental and economical character.Attention is paid to the hemodynamic disorders assessment (vascularization of the lower uterus) in pregnant women and determination of their role in the fetoplacental dysfunction development. The role of the hemodynamic disorders in the placenta is considered as the morphological and biochemical adaptive reactions abnormality.

FARE GEBELİK DÖNEMİNDE HAREKETSİZLİK STRESİNİN PLASENTA VE YAVRUYA ETKİLERİ

ABSTRACT AIM: Stress can affect negatively mother and fetuses during pregnancy. We aimed to investigate the effects of chronic immobilization stress on placental maturation and fetal development.MATERİALS AND METHODS: Balb/c virgin female mice (20-30 g) were mated with male mice in a 2 to 1 female to male ratio. Pregnant mice in control group (n=6) were left undisturbed, whereas pregnant mice in the stress group (n=6) were exposed to 45 min chronic immobilization stress for three times/day starting from gestational day 6 till 18. Fetuses and placentas were removed from dams on the gestational day 18 under anesthesia.RESULTS: The prenatal stress significantly increased apoptosis in several placental cells including trophoblastic giant cells, glycogen cells and labyrinth trophoblastic cells and resulted in intrauterine growth restriction. The stress caused a decreased superoxide dismutase and glutathione levels. Alizarin Red S staining shows the ossification center of the fetuses to see developmental abnormality. CONCLUSION: Gestational stress causes placental dysfunctions by triggering apoptosis, reducing the labyrinth zone as well as increasing collagen levels, which may impair fetal development that may contribute to pathogenesis of intrauterine growth restriction.

Sex differences in uterine artery Doppler during gestation in pregnancies complicated by placental dysfunction

BackgroundThere is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies.MethodsA prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope.ResultsWhile the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation.ConclusionsThe uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Third Trimester Placental Grading by Ultrasonography and its Relationship with Fetal Outcome

Background: Antenatal ultrasound assessment of placental morphology plays an important role in evaluating fetal health, revealing abnormalities, such as infract &amp; calcification. Abnormal placental maturity is associated with poor pregnancy outcome. In some high risk pregnancy placental maturity is accelerated as in pregancy –induced hypertension (PIH), intrauterine growth retardation (IUGR), whether in other high risk cases like diabetes and Rh-isoimmunization there is delayed placental maturation.&#x0D; Objectives: This was a cross sectional type of descriptive study. The study was carried out to assess placental grading by USG in high risk and normal pregnancy for predicting neonatal outcome.&#x0D; Material and method: The study was carried out in the Department of Obstetrics &amp; Gynaecology in collaboration with the Department of Radiology &amp; Imaging of Rajshahi Medical College Hospital from January 2012 to December 2013. : A total 200 pregnant mother, attending the inpatient department constituted study population who delivered their babies at Rajshahi Medical College Hospital were selected in antenatal period for USG examination to detect placental grade.&#x0D; Result: Ultrasonography showed, 35% had Grade-II placental maturity, 33.5%- Grade-III, 25% Grade - I and 6.5% had Grade-0 maturity. Majority of the mother (75%) were normal and had healthy baby. The relationship of placental maturity with gestational age of mother in normal pregnancy and in high risk pregnancy was found to be statistically significant. Placental maturity and fetal outcome in normal pregnancy was found significantly associated (p&lt;0.001) but in high risk pregnancy it was not associated significantly (p&gt;0.5). Early maturation of placenta in hypertensive women and delayed maturation in diabetic women were observed.&#x0D; Conclusion: Sonographic diagnosis of grade-III placenta has been reported to be as excellent predictor of fetal lung maturity than difficult and hazardous invasive procedure like amniocentesis.&#x0D; TAJ 2020; 33(2): 94-99

Endothelial dysfunction and its role in the prevention, treatment and complications of critical conditions in obstetrics

Background. Preeclampsia (PE) remains the leading cause of maternal and perinatal morbidity and mortality. As of today, there is no treatment for PE, and the childbirth is the only way to completely eliminate this condition. However, early childbirth is associated with a high risk of fetal morbidity and mortality.&#x0D; Objective. To describe the role of endothelial dysfunction (ED) in the development of PE and the possibility of its correction; to evaluate the effectiveness of Tivortin (“Yuria-Pharm”) in the correction of uterine-fetal-placental dysfunction.&#x0D; Materials and methods. Analysis of literature sources on this topic; own PLACENTA study. The study involved 535 women with mild PE at 26-29 weeks of gestation. Group I received standard therapy, group II – standard therapy in combination with Tivortin (4.2 g per day for 7-10 days).&#x0D; Results and discussion. Until the fetus reaches viability, PE treatment is aimed at correcting hypertension, however, antihypertensive therapy does not have a beneficial effect on the condition of the kidneys and placental blood flow. Decreased blood flow in placenta leads to the syndrome of limited fetal development (SLFD) and multisystem ED. The development of PE is inextricably linked with the systemic damage to maternal endothelial cells and a further decrease in endothelium-dependent vasodilators, which promotes vasospasm and activates the coagulation cascade. PE is accompanied by the imbalance in the systems of prostacyclin and nitric oxide (NO), as well as thromboxane and endothelin. Superficial placentation with insufficient remodeling of the spiral arteries and impaired response to changes in blood flow is one of the main causes of PE. ED is the most studied pathogenetic mechanism of PE. NO has a potent vasodilating effect and is involved in inhibiting thromboxane formation, platelet aggregation and stimulating prostacyclin formation. NO-synthase of endothelial cells, the substrate of which is L-arginine, is the main enzyme of NO production. Disorders of vasodilation in pregnant women with PE can be eliminated by prescribing L-arginine. Literature data show that L-arginine is successfully used in the need to continue pregnancy, as well as to eliminate hypertension and correct SLFD. Canadian guidelines for the treatment of hypertensive complications of pregnancy state that L-arginine is able to improve uteroplacental blood flow. According to a study by J. Chen (2016), the inclusion of L-arginine contributes to both maternal and perinatal outcomes of pregnancy. The effect of L-arginine on fetal growth is mediated by promoting the production of creatine, skeletal muscle protein and growth hormone. L-arginine also promotes the synthesis of polyamines, which can stimulate the growth and development of placenta. Own studies have shown that the use of L-arginine (Tivortin, “Yuria-Pharm”) in the combined PE therapy had improved the growth rate of the fetus and its functional condition, which allowed to prolong pregnancy to the optimal term of childbirth, as well as improve the consequences of childbirth and adaptation of newborns in the early neonatal period. PE is not the only field of application of Tivortin: its intravenous administration in community-acquired pneumonia and pyelonephritis of pregnant women helps to quickly eliminate the pathological process. The results of the PLACENTA study found that Tivortin helped to improve uterine-fetal-placental blood flow and reduce the centralization of blood circulation. In the Tivortin group there was a smaller number of cesarean sections, a tendency to lower blood loss (by 19.5 %), a higher average score of newborns on the Apgar scale. Comparison of clinical and morphological changes showed that the administration of Tivortin in the late second and early third trimester of pregnancy reduces the likelihood of premature placental maturation by 2.1 %, halves the likelihood of placental necrosis, 10 times reduces the signs of hypoxia.&#x0D; Conclusions. 1. ED, caused by a decrease in NO, is the main link in the PE pathogenesis. 2. In the human body NO is produced from L-arginine. 3. The use of L-arginine (Tivortin) improves uterine-fetal-placental blood flow, growth rate and functional status of the fetus, reduces fetal distress and allows to prolong pregnancy to the optimal term of childbirth.

The diagnostic value of two-dimensional shear wave elastography in gestational diabetes mellitus

ObjectiveThe aim of our study is to establish the reference range of Young's modulus values of placenta in normal pregnancies and to evaluate the diagnostic value of two-dimensional shear wave elastography (2D-SWE) in gestational diabetes mellitus (GDM). MethodsA total of 223 normal pregnant women, 22 pregnancies complicated by A1GDM (controlled by diet), and 14 pregnancies complicated by A2GDM (controlled by medication) were recruited for this study. The elasticity values of the central parts of the placentas were determined by 2D-SWE imaging. The mean value (Emean), min value (Emin), and max value (Emax) of the placentas were recorded. Twenty placentas were randomly selected for reliability analysis. Results(1) All values (Emean, Emin, Emax) showed great repeatability and consistency. (2) The reference range of Young's modulus values of placentas in normal pregnancies were Emean (4.12 ± 0.83), Emin (2.15 ± 0.83) and Emax (6.72 ± 1.43). No significant correlations were observed between elasticity values and gestational age (r < 0.3, p > 0.05) or between elasticity values and placental maturity (r < 0.3, p > 0.05). (3) The Young's modulus values in the A1 GDM and A2 GDM women were Emean (6.39 ± 1.74), Emin (2.95 ± 1.05), Emax (10.78 ± 2.94) and Emean (11.96 ± 7.29), Emin (6.79 ± 4.70a), Emax (18.94 ± 11.61) respectively. All values were significantly higher in GDM pregnancies than in normal pregnancies (p < 0.05). A2GDM pregnancies had higher values than A1GDM pregnancies (p < 0.05). ConclusionPlacental elasticity is independent of gestational age and placental maturity. 2D-SWE can play an important role in diagnosing GDM by assessing placental hardness.

Hybrid descriptor for placental maturity grading

Placental maturity grading (PMG) is quite essential to assess fetal growth and maternal health. To this date, PMG has mostly relied on the subjective judgment of the clinician, which is time-consuming and may cause wrong estimation due to redundancy and repeatability of the process. To tackle it, we propose an automatic method to stage placental maturity via deep hybrid descriptors based on B-mode ultrasound (BUS) and color Doppler energy (CDE) images. Specifically, convolutional descriptors extracted from multiple deep convolutional neural networks (DCNNs) and hand-crafted features are integrated to get the hybrid descriptors for grading performance boosting. First, different models with various feature layers are combined to obtain hybrid descriptors from images. Second, the transfer learning strategy is also utilized to enhance the grading performance via the deeply represented features. Third, extracted descriptors are encoded by Fisher vector (FV). Finally, we use support vector machine (SVM) as the classifier to grade placental maturity. The experimental results demonstrate that our proposed method could achieve good performance in PMG.

Disorders of placental villous maturation in fetal death.

Objective The aims of this study were to ascertain the frequency of disorders of villous maturation in fetal death and to also delineate other placental histopathologic lesions in fetal death. Methods This was a retrospective observational cohort study of fetal deaths occurring among women between January 2004 and January 2016 at Hutzel Women's Hospital, Detroit, MI, USA. Cases comprised fetuses with death beyond 20 weeks' gestation. Fetal deaths with congenital anomalies and multiple gestations were excluded. Controls included pregnant women without medical/obstetrical complications and delivered singleton, term (37-42 weeks) neonate with 5-min Apgar score ≥7 and birthweight between the 10th and 90th percentiles. Results Ninety-two percent (132/143) of placentas with fetal death showed placental histologic lesions. Fetal deaths were associated with (1) higher frequency of disorders of villous maturation [44.0% (64/143) vs. 1.0% (4/405), P < 0.0001, prevalence ratio, 44.6; delayed villous maturation, 22% (31/143); accelerated villous maturation, 20% (28/143); and maturation arrest, 4% (5/143)]; (2) higher frequency of maternal vascular malperfusion lesions [75.5% (108/143) vs. 35.7% (337/944), P < 0.0001, prevalence ratio, 2.1] and fetal vascular malperfusion lesions [88.1% (126/143) vs. 19.7% (186/944), P < 0.0001, prevalence ratio, 4.5]; (3) higher frequency of placental histologic patterns suggestive of hypoxia [59.0% (85/143) vs. 9.3% (82/942), P < 0.0001, prevalence ratio, 6.8]; and (4) higher frequency of chronic inflammatory lesions [53.1% (76/143) vs. 29.9% (282/944), P < 0.001, prevalence ratio 1.8]. Conclusion This study demonstrates that placentas of women with fetal death were 44 times more likely to present disorders of villous maturation compared to placentas of those with normal pregnancy. This suggests that the burden of placental disorders of villous maturation lesions is substantial.

Amniotic fluid cell-free transcriptome: a glimpse into fetal development and placental cellular dynamics during normal pregnancy

BackgroundThe amniotic fluid (AF) cell-free transcriptome is modulated by physiologic and pathologic processes during pregnancy. AF gene expression changes with advancing gestation reflect fetal development and organ maturation; yet, defining normal expression and splicing patterns for biomarker discovery in obstetrics requires larger heterogeneous cohorts, evaluation of potential confounding factors, and novel analytical approaches.MethodsWomen with a normal pregnancy who had an AF sample collected during midtrimester (n = 30) or at term gestation (n = 68) were included. Expression profiling at exon level resolution was performed using Human Transcriptome Arrays. Differential expression was based on moderated t-test adjusted p < 0.05 and fold change > 1.25; for differential splicing, a splicing index > 2 and adjusted p < 0.05 were required. Functional profiling was used to interpret differentially expressed or spliced genes. The expression of tissue-specific and cell-type specific signatures defined by single-cell genomics was quantified and correlated with covariates. In-silico validation studies were performed using publicly available datasets.Results1) 64,071 genes were detected in AF, with 11% of the coding and 6% of the non-coding genes being differentially expressed between midtrimester and term gestation. Expression changes were highly correlated with those previously reported (R > 0.79, p < 0.001) and featured increased expression of genes specific to the trachea, salivary glands, and lung and decreased expression of genes specific to the cardiac myocytes, uterus, and fetal liver, among others. 2) Single-cell RNA-seq signatures of the cytotrophoblast, Hofbauer cells, erythrocytes, monocytes, T and B cells, among others, showed complex patterns of modulation with gestation (adjusted p < 0.05). 3) In 17% of the genes detected, we found differential splicing with advancing gestation in genes related to brain development processes and immunity pathways, including some that were missed based on differential expression analysis alone.ConclusionsThis represents the largest AF transcriptomics study in normal pregnancy, reporting for the first time that single-cell genomic signatures can be tracked in the AF and display complex patterns of expression during gestation. We also demonstrate a role for alternative splicing in tissue-identity acquisition, organ development, and immune processes. The results herein may have implications for the development of fetal testing to assess placental function and fetal organ maturity.

Histological villous maturation in placentas of complicated pregnancies.

Chorioamnionitis and preeclampsia account for the majority of preterm births worldwide. Thus far, adequate methods for early detection or prevention of these diseases are lacking. In preeclampsia, accelerated villous maturation is believed to compensate placental insufficiency. However, little is known about the effects of placental inflammation in chorioamnionitis on villous maturation. Therefore, we established a set of morphological parameters to evaluate histological villous maturity in pregnancies complicated by chorioamnionitis and preeclampsia. Preterm placentas complicated by chorioamnionitis or preeclampsia were compared to idiopathic preterm placentas and term controls. Histological villous maturation was analyzed by means of 17 histological markers. Fourteen of these markers provided information on absolute and relative numbers of the terminal villi (TV), the extent of their vascularization (using CD31-stained sections) and their exchange capacities. In addition, the numbers of syncytial bridges, syncytial apoptotic knots and shed syncytiotrophoblasts were counted. Accelerated villous maturation in preeclampsia was demonstrated by means of histological villous remodeling and confirmed by 11 relevant markers. Chorioamnionitis, however, only showed increased area of fetal capillaries. In preeclampsia, placentas may transition from growth to maturation earlier than placentas in normal pregnancies, whereas in chorioamnionitis placental changes are more acute and therefore less elaborated at a structural level. Regression analysis suggests the number of all villi and the number of terminal villi as a percentage of all villi as parameters to evaluate histological villous maturity in preeclamptic placentas and to assist diagnosis. However, we would recommend to analyze all 11 relevant parameters to judge placental maturity in detail.

449: Longitudinal measurements of proprotein convertase subtilisin kexin 9 (PCSK-9) in patients with and without preeclampsia

Cholesterol (CHOL) synthesis is necessary for healthy fetal and placental maturation and growth in pregnancy, and adverse pregnancy outcomes (APO) have been identified in women with significantly elevated or depressed lipid profiles. Proprotein convertase subtilisin kexin 9 (PCSK-9) enzyme degrades the low density receptor (LDL)-receptor found in hepatic and endothelial tissue, thus increases serum LDL through decreased receptor binding and is a surrogate marker for CHOL metabolism. Elevated PCSK-9 levels are associated with hypercholesterolemia and atherosclerosis but its characteristics during pregnancy are not well established. Our goal was to measure PCSK-9 during and late after normal and preeclamptic pregnancy to characterize biomarker levels associated with normal and abnormal pregnancy. We performed a single institution prospective cohort study. Inclusion criteria were women with singleton pregnancies > 23 weeks and diagnosis of preeclampsia with severe features (PEC), per ACOG guidelines. Controls were women with uncomplicated singleton gestations > 23 weeks. We excluded women with known hyperlipidemia. Longitudinal data were collected during pregnancy (2015) and non-pregnancy 4 years later (2019). Statistical analyses were performed using a paired t-test for longitudinal data, and all parametric and nonparametric data were analyzed appropriately with Graphpad, Version 8. The sample size was adequate to detect significance at p< 0.05 with a power of 80%. Demographic characteristics between groups were similar except for race (Table). There was a statistically significant decrease in longitudinal PCSK-9 levels from pregnancy to 4 year follow up (non-pregnancy), (114 (32.3) vs 63 (11.3), p=0.004). In contrast, this longitudinal decrease was not observed in patients with preeclampsia, (83 (19.0) vs 75 (24.4), p=0.381). (Figure) PCSK-9 levels are higher during normal pregnancy than in the non-pregnant state. However, patients with PEC do not have a higher level. PCSK-9 and CHOL metabolism should be further evaluated for associations with APO.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Unique transcriptomic landscapes identified in idiopathic spontaneous and infection related preterm births compared to normal term births.

Preterm birth (PTB) is leading contributor to infant death in the United States and globally, yet the underlying mechanistic causes are not well understood. Histopathological studies of preterm birth suggest advanced villous maturity may have a role in idiopathic spontaneous preterm birth (isPTB). To better understand pathological and molecular basis of isPTB, we compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB between 28–36 weeks gestation and healthy term placentas. Transcriptomic analyses revealed a unique expression signature for isPTB distinct from the age-matched controls that were delivered prematurely due to infection. This signature included the upregulation of three IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB. However, within the isPTB expression signature, we detected secondary signature of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the gestational age-matched infected samples included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth.

Biological importance of podoplanin expression in chorionic villous stromal cells and its relationship to placental pathologies

Podoplanin, a reliable marker of lymphatic endothelium, is a mucin-type transmembrane protein. Although the human placenta is devoid of a lymphatic system, chorionic villous stromal (CVS) cells express podoplanin. In this study, the pattern of podoplanin expression in normal and pathological placental tissues and the biological role of podoplanin were investigated. In total, 198 placental tissues belonging to 184 patients, seen at the Department of Pathology of Bulent Ecevit University Education and Research Hospital, Zonguldak, Turkey, were evaluated histopathologically and determined to meet the study criteria. The tissues were assigned to control, cisternal placental disorders, inflammation and hypoxic-ischemic pathology groups. Podoplanin expression in CVS cells was graded from 0 to 3 depending on the staining intensity, as determined by an immunohistochemical evaluation of chorionic villi in the most intensively stained tissue region. Podoplanin levels in control CVS cells increased in parallel with placental maturation, whereas in molar pregnancies podoplanin expression was lower than in control tissues. In the acute placental inflammation group, podoplanin immunoreactivity was similar to that in the control group, whereas in the preeclampsia group, podoplanin expression was higher than in all other groups. Our study showed an increase in podoplanin expression in CVS cells during pregnancy. In preeclamptic patients, the increase in podoplanin expression may be a response to hypoxic-ischemic conditions, whereas in molar pregnancies the decrease in podoplanin levels may cause villous swelling by disrupting intercellular fluid homeostasis.

In Utero Diffusion MRI: Challenges, Advances, and Applications.

In utero diffusion magnetic resonance imaging (MRI) provides unique opportunities to noninvasively study the microstructure of tissue during fetal development. A wide range of developmental processes, such as the growth of white matter tracts in the brain, the maturation of placental villous trees, or the fibers in the fetal heart remain to be studied and understood in detail. Advances in fetal interventions and surgery furthermore increase the need for ever more precise antenatal diagnosis from fetal MRI. However, the specific properties of the in utero environment, such as fetal and maternal motion, increased field-of-view, tissue interfaces and safety considerations, are significant challenges for most MRI techniques, and particularly for diffusion. Recent years have seen major improvements, driven by the development of bespoke techniques adapted to these specific challenges in both acquisition and processing. Fetal diffusion MRI, an emerging research tool, is now adding valuable novel information for both research and clinical questions. This paper will highlight specific challenges, outline strategies to target them, and discuss two main applications: fetal brain connectomics and placental maturation.