Uteroplacental Interface Research Articles

Knowledge-guided Pretext Learning for Utero-placental Interface Detection.

Modern machine learning systems, such as convolutional neural networks rely on a rich collection of training data to learn discriminative representations. In many medical imaging applications, unfortunately, collecting a large set of well-annotated data is prohibitively expensive. To overcome data shortage and facilitate representation learning, we develop Knowledge-guided Pretext Learning (KPL) that learns anatomy-related image representations in a pretext task under the guidance of knowledge from the downstream target task. In the context of utero-placental interface detection in placental ultrasound, we find that KPL substantially improves the quality of the learned representations without consuming data from external sources such as IMAGENET. It outperforms the widely adopted supervised pre-training and self-supervised learning approaches across model capacities and dataset scales. Our results suggest that pretext learning is a promising direction for representation learning in medical image analysis, especially in the small data regime.

MRI prognosticators for adverse maternal and neonatal clinical outcome in patients at high risk for placenta accreta spectrum (PAS) disorders.

Placenta accreta spectrum (PAS) disorders may be associated with significant mortality and morbidity for both mother and fetus. To identify MRI risk factors for poor peripartum outcome in gravid patients at risk for PAS. Prospective. One hundred gravid women (mean age: 34.9 years) at third trimester, with placenta previa. T2 -SSTSE (single-shot turbo spin echo), T2 -TSE, T1 -TSEFS (TSE images with fat-suppression) at 1.5T. Fifteen MRI features considered indicative of PAS were recorded by three radiologists and were tested for any association with the following adverse peripartum maternal and neonatal events: increased operation time, profound blood loss, hysterectomy, bladder repair, ICU admission, prematurity, low birthweight, and 5-minute APGAR score <7. Kappa (K) coefficients were computed as a measure of agreement between intraoperative information/histology and MRI results as well as for interobserver agreement; chi-square and Fisher's exact tests were used to explore the association of the MRI signs with clinical complications. A score was calculated by adding all recorded MRI signs and its predictive ability was tested using receiver operating characteristic (ROC) analysis, against all complications, separately; odds ratios (ORs) for optimal cutoffs were determined with logistic regression analysis. There was excellent agreement (K >0.75, P < 0.001) between MRI and intraoperative findings for invasive placenta, bladder and parametrial involvement. Intraplacental T2 dark bands, myometrial disruption, uterine bulge, and hypervascularity at the utero-placental interface or parametrium, showed significant association (P < 0.005) with poor clinical outcome for both mother and fetus. The MRI score showed significant predictive ability for each adverse maternal event (area under the curve [AUC]: 0.85-0.97, P < 0.001). The presence of ≥3 MRI signs was the cutoff point for a complicated delivery (OR: 19.08, 95% confidence interval [CI]: 6.05-60.13) and ≥6 MRI signs was the cutoff point for massive bleeding (OR: 90.93, 95% CI: 11.3-729.23), hysterectomy (OR: 72.5, 95% CI: 17.9-293.7), or extensive bladder repair (OR: 58.74, 95% CI: 7.35-469.32). The MRI score was not significant for predicting adverse neonatal events including preterm delivery (P = 0.558), low birthweight (P = 0.097), and 5-minute Apgar score (P = 0.078). Preoperative identification of specific MRI features may predict peripartum course in high-risk patients for PAS. 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;50:602-618.

Placental implantation over prior cesarean scar causes activation of fetal regulatory T cells.

IntroductionMaternal‐fetal chimerism is miniscule, a testament to the integrity of the uteroplacental interface. The soundness of this border region is potentially altered through cesarean delivery of prior babies with uncertain consequences for the following pregnancies.MethodsUsing multicolor flow cytometry and quantitative PCR of non‐inherited maternal antigens we performed a retrospective case control pilot study and formulated the null hypothesis that placental implantation over a prior uterine scar does not result in the presence of memory Treg (CD45RO+) in the fetus. We then performed a power calculation and performed a blinded, appropriately powered prospective case control study to test the null hypothesis.ResultsFetuses born to mothers with prior uterine scar have a roughly five times higher maternal to fetal microchimerism when the placenta directly interacts with the uterine scar. Unlike exposure to antigens in adult life, in utero antigenic exposure induces tolerogenic (Treg) responses in fetuses and we here report the presence of fetal Treg with a memory phenotype (CD45RO+). However, we only find such CD45RO+ fetal Tregs when the placenta abuts the uterine scar (Risk Ratio = 5 [p < 0.05 CI:(1.448 to 17.27)]). These memory fetal Tregs are functionally highly suppressive compared to CD45RA‐expressing fetal Tregs, and have specificity for non‐inherited maternal antigens.ConclusionsWe found that uterine scars, in the case of our study these scars are from prior c‐sections, fundamentally impair uterine integrity allowing for increased antigen exposure of the fetus; with our appropriately powered study we rejected the null hypothesis and accepted the alternative hypothesis that placental implantation over a prior uterine scar results in the presence of memory Treg (CD45RO+) in the fetus. Thus, our study demonstrates a previously unappreciated role for uterine integrity in limiting fetal antigenic exposure, a key element to avoid the formation of inappropriate tolerances by the fundamentally tolerogenic fetal immune system.

Automated Visualization and Quantification of Spiral Artery Blood Flow Entering the First-Trimester Placenta, Using 3-D Power Doppler Ultrasound

The goal of our research was to quantify the placental vascularity in 3-D at 11–13 + 6 wk of pregnancy at precise distances from the utero-placental interface (UPI) using 3-D power Doppler ultrasound. With this automated image analysis technique, differences in vascularity between normal and pathologic pregnancies may be observed. The algorithm was validated using a computer-generated image phantom and applied retrospectively in 143 patients. The following features from the PD data were recorded: The number of spiral artery jets into the inter-villous space, total geometric and PD area. These were automatically measured at discrete millimeter distances from the UPI. Differences in features were compared with pregnancy outcomes: Pre-eclamptic versus normal, all small-for-gestational age (SGA) to appropriate-for-gestational age (AGA) patients and AGA versus SGA in normotensives (Mann-Whitney). The Benjamini-Hochberg procedure was used (false discovery rate 10%) for multiple comparison testing. Features decreased with increasing distance from the UPI (Kruskal-Wallis test; p < 0.001). At 2– 3 mm from the UPI, all features were smaller in pre-eclamptic compared with normal patients and for some in SGA compared with AGA patients (p < 0.05). For AGA versus SGA in normotensive patients, no significant differences were found. Number of jets measured at 2–5 mm from the UPI did not vary because of the position of the placenta in the uterus (ANOVA; p > 0.05). This method provides a new in-vivo imaging tool for examining spiral artery development through pregnancy. Size and number of entrances of blood flow into the UPI could potentially be used to identify high-risk pregnancies and may provide a new imaging biomarker for placental insufficiency.

187: Proteomic changes of placental and myometrial tissue in placenta accreta

Placenta accreta is associated with a significant risk of maternal hemorrhage, morbidity and mortality. Despite the increasing incidence of this condition, the molecular alterations associated with accreta at the utero-placental interface are poorly understood. The objective of this study was to use proteomics to characterize myometrial and placental compartments among accreta patients. We identified cesarean hysterectomy specimens from 85 accreta patients and 14 control patients with uterine atony. Uterine myometrial (n=99) and trophoblast (n=99) cells from accreta and control patients were discretely harvested by lasermicrodissection, digested, and analyzed by mass spectrometry. Protein abundances were estimated using spectral counting and significant differences in abundance from control specimens were determined. Multivariate and leave-one-out analysis were used to develop classifiers and assess performance for select comparisons. Proteomic data from 35 accreta, 44 increta, 18 percreta, and 14 control patients were compared. Unsupervised analysis demonstrated perfect clustering of proteomic data from myometrial vs placental compartments across the 198 specimens. Comparison of accreta, increta, and percreta vs control revealed 26 common placental proteins (p<0.05)and 136 common myometrial proteins (p<0.05), respectively. KRT7 and PRG2 are two notable myometrial proteins that were elevated >5-fold with p<2x10-7. Pathway analysis of the 136 accreta-associated myometrial proteins revealed immune function and cellular motility as predominant categories of dysregulation. Proteomic classifier models revealed an AUC of 0.88 for accreta vs increta/percreta and AUC of 1.0 for increta/percreta versus control. Proteomic analysis revealed more differentially expressed proteins in the myometrial compartment compared to the placental tissue among patients with accreta. This inventory of proteins warrants future investigation for diagnostic and therapeutic applications.

Critical care in obstetrics.

Pregnancy is a normal physiologic process with the potential for pathologic states. Pregnancy has several unique characteristics including an utero-placental interface, a physiologic stress that can cause pathologic states to develop, and a maternal–foetal interface that can affect two lives simultaneously or in isolation. Critical illness in pregnant women may result from deteriorating preexisting conditions, diseases that are co-incidental to pregnancy, or pregnancy-specific conditions. Successful maternal and neonatal outcomes for parturients admitted to a maternal critical care facility are largely dependent on a multidisciplinary input to medical or surgical condition from critical care physicians, obstetric anaesthesiologists, obstetricians, obstetric physicians, foetal medicine specialists, neonatologists, and concerned specialists. Pregnant women requiring maternal critical care unit admission are relatively low in developed nations and range from 0.9% to 1%; but in our country, the admission rates of critically ill parturients range from 3% to 8%. Two-thirds of pregnant women requiring critical care are often unanticipated at the time of conception. In this review, we will look at critical illnesses in pregnant women with a specific focus on pregnancy-induced illnesses.

Maternal-Fetal rejection reactions are unconstrained in preeclamptic women.

The risk factors for preeclampsia, extremes of maternal age, changing paternity, concomitant maternal autoimmunity, and/or birth intervals greater than 5 years, suggest an underlying immunopathology. We used peripheral blood and lymphocytes from the UteroPlacental Interface (UPI) of 3rd trimester healthy pregnant women in multicolor flow cytometry—and in vitro suppression assays. The major end-point was the characterization of activation markers, and potential effector functions of different CD4—and CD8 subsets as well as T regulatory cells (Treg). We observed a significant shift of peripheral CD4 –and CD8- T cells from naïve to memory phenotype in preeclamptic women compared to healthy pregnant women consistent with long-standing immune activation. While the proportions of the highly suppressive Cytokine and Activated Treg were increased in preeclampsia, Treg tolerance toward fetal antigens was dysfunctional. Thus, our observations indicate a long-standing inflammatory derangement driving immune activation in preeclampsia; in how far the Treg dysfunction is caused by/causes this immune activation in preeclampsia will be the object of future studies.

The importance of bladder volume in the ultrasound diagnosis of placenta accreta spectrum disorders.

To assess how a quantifiable measure of vascularity-i.e. abnormal confluence (Acon ) in the subplacental myometrium observed by three-dimensional power-Doppler ultrasonography-changes with different bladder volumes. In a prospective observational study, women referred to a tertiary UK center with suspected PAS disorders were recruited between August 2016 and May 2017. The largest area of confluent three-dimensional power-Doppler signal (Acon ) at the uteroplacental interface was estimated under two bladder volumes differing by at least 200mL. Acon was calculated for 14 women, of whom seven were subsequently found to have PAS disorders. For these seven women, log(Acon ) was significantly greater when measured with a filled bladder than when measured with an unfilled bladder (P<0.001). Objective evidence was found for a quantifiable difference in vascularity in the myometrium with bladder volume among women with PAS disorders. This difference has sufficient magnitude to influence the potential of Acon as a diagnostic marker.

Understanding the immune microenvironment at the uteroplacental interface

Understanding the immune microenvironment at the uteroplacental interface

Hybrid foetus with an FE head for a pregnant occupant model for vehicle safety investigations

ABSTRACT‘Expecting’, a computational pregnant occupant model, developed to simulate the dynamic response to crash impacts, possesses anthropometric properties of a fifth percentile female at around the 38th week of pregnancy. The model is complete with a finite element uterus and a multi-body foetus which is a novel feature in models of this kind. In this paper, the effect of incorporating a foetus with a finite element head into ‘Expecting’ is investigated. The finite element head was developed using detailed anatomic geometry and projected material properties. Then it was integrated with the ‘Expecting’ model and validated using the lap belt loading and the rigid bar impact tests. The model is then used to simulate frontal impacts at a range of crash severities with seatbelt and airbag, seatbelt only, airbag only as well as no restraint cases to investigate the risk of placental abruption and compare it with the model featuring the original multi-body foetus. The maximum strains developed in the utero-placental interface are used as the main criteria for foetus safety. The results show comparable strain levels to those from the multi-body foetus. It is, therefore, recommended to use the multi-body foetus in simulations as the computation time is more favourable.

Thrombin-Induced Inflammation in Human Decidual Cells Is Not Affected By Heparin

Thrombin (Thr) generation at the uteroplacental interface induces inflammation and weakens fetal membranes. Tissue factor (TF) is a powerful procoagulant that is increased by Thr in decidual cells (DCs). The TF expression may play an important role in modulating Thr-induced inflammation. The purpose of this study was to assess the effect of heparin, including nonanticoagulant (desulfated) heparins, on basal and Thr-induced expression of TF and inflammatory cytokines in DCs. Fetal membranes were collected from term pregnancies undergoing unlabored cesarean delivery and then DCs were isolated and cultured. Third passage DCs were conditioned in defined media for 1 week and then treated with 1 of the 4 heparins (enoxaparin, unfractionated heparin, and 2 desulfated heparins) with and without Thr (2.5 U/mL) for 24 hours. Supernatant levels of interleukin (IL) 6, IL-8, IL-10, tumor necrosis factor α, and interferon γ (IFN-γ) were determined by enzyme-linked immunosorbent assay. Western blots were performed on cell lysates to determine TF expression. A Kruskal-Wallis test was used to compare cytokine concentrations and normalized TF expression among treatments. Treatment of DCs with Thr alone increased the expression of TF, IL-6, IL8, IL-10, and IFN-γ compared to basal levels ( P < .05 for each). Cotreatment of DCs with Thr and any of the tested heparins did not decrease the expression of TF or inflammatory cytokines compared to treatment with Thr alone. Heparins do not appear to affect basal or Thr-induced expression of TF or inflammatory cytokines in human term DCs. Additional work is needed to determine whether nonanticoagulant heparins can reduce inflammation and membrane weakening due to bleeding in pregnancy.

3D fractional moving blood volume (3D-FMBV) demonstrates decreased first trimester placental vascularity in pre-eclampsia but not the term, small for gestation age baby.

ObjectiveTo undertake an observational study to see whether first trimester placental vascularity, measured with a standardized power Doppler index: 3D-FMBV, is different in pregnancies which either develop pre-eclampsia or lead to term, normotensive small for gestational age (SGA) babies.MethodsWomen were scanned between 11 and 13+6 weeks. The placental volume (sPlaV) was estimated using our previously validated semi-automated tool. Estimates of 3D-FMBV were generated from the raw power Doppler signal for the whole utero-placental interface, UPI (FMBV-UPI) and 5mm into the placenta (FMBV-IVS). Differences in the placental volume and FMBV for pregnancies developing pre-eclampsia and resulting in term, normotensive SGA babies were compared with term, normotensive, appropriate for gestational age (AGA), controls.ResultsResults were available for 143 women. The placental volume (sPlaV) was reduced in both pre-eclampsia (p = 0.007) and term, normotensive SGA (p = 0.001) when compared with term normotensive AGA controls. 3D-FMBV estimates were significantly lower for pregnancies developing pre-eclampsia (FMBV-UPI, p = 0.03, FMBV-IVS, p = 0.01) but not for the normotensive SGA pregnancies (FMBV-UPI, p = 0.16, FMBV-IVS, p = 0.27).ConclusionPregnancies destined to develop pre-eclampsia are more likely to have small placentas with significantly reduced vascularity at 11–13 weeks. Those pregnancies which were normotensive throughout but resulted in an SGA baby delivered at term, had significantly smaller placentas but with similar vascularity to normotensive AGA pregnancies.

Effect of Cytokines on the Formation Tube-Like Structures by Endothelial Cells in the Presence of Trophoblast Cells.

Despite ample data on cytokine secretion in the uteroplacental interface, the influence of microenvironment cells, in particular, trophoblast cells on angiogenesis and the role of cytokines in this process remain poorly studied. We studied the influence of cytokines on the formation of tube-like structures by endothelial cells in the presence of trophoblast cells and showed that trophoblast cells suppressed the angiogenic potential of endothelial cells. Antiangiogenic cytokines IFN-γ, IL-10, TNF-α, and TGFβ via modulation of trophoblast cells stimulated the formation of tube-like structures by endothelial cells. In the co-culture of endothelial and trophoblast cells, the effects of cytokines changed and they gained additional regulatory functions.

The effect of placenta location on the safety of pregnant driver and her fetus

ABSTRACTPlacental abruption accounts for more than half of fetal mortality in automobile collisions. In most of the pregnancies, placenta is located at the fundus position of the uterus. However, in real life, placenta can also be found at different locations in the uterus.The goal of this study is to investigate whether the location of the placenta in the uterus of pregnant driver has a role on the risk of placental abruption in motor vehicle accidents. In addition to the most common fundus position, four other placental locations, namely anterior, posterior, lateral left and lateral right, are considered within the computational pregnant driver model ‘Expecting’, and used in collision simulations with impact severities from 15 to 30 kph with 5-kph increments. Scenarios also include four cases where the pregnant driver is fully restrained with three-point seatbelt and airbag, three-point seatbelt only, airbag only and no restraint at all. The maximum strains developed in the utero-placental interface of the model in this set of 64 simulations together with the fundus-location simulations are determined and compared in order to investigate the effect of placental location on the placental abruption prediction.Placenta located at anterior position is found to be at higher risk than other placental positions considered in this investigation. The results demonstrate that being fully restrained is the safest option and the three-point seatbelt is the most effective restraint system whilst the airbag makes a small contribution to the protection of pregnant driver and her fetus.

Prediction of morbidly adherent placenta using a scoring system

To evaluate the accuracy of an ultrasound-based scoring system for diagnosing morbidly adherent placenta (MAP). This study included pregnant women referred to our ultrasound unit during 2013-2015 because of suspected MAP on a previous ultrasound examination or because they had at least one previous Cesarean delivery. All women were assessed using a scoring system based on the following: number and size of placental lacunae; obliteration of the demarcation between the uterus and placenta; placental location; color Doppler signals within placental lacunae; hypervascularity of the placenta-bladder and/or uteroplacental interface zone; and number of previous Cesarean deliveries. Each criterion was assigned 0, 1 or 2 points and the sum of points yielded the final score. Patients were classified into low, moderate or high probability for MAP based on the final score. The presence of MAP was determined by the surgeon at delivery and clinical descriptions were documented in the electronic patient file. Pathological diagnoses were available only in cases that underwent hysterectomy. In total, 258 pregnant women were included in the study, of whom 23 (8.9%) were diagnosed with MAP. There was a statistically significant difference in the prevalence of MAP when women were grouped according to the scoring system, with 0.9%, 29.4% and 84.2% in the low, moderate and high probability groups, respectively (P < 0.0001). All sonographic criteria of the scoring system were significantly associated with MAP (P < 0.0001). Receiver-operating characteristics (ROC) curves for prediction of MAP using the number of placental lacunae and obliteration of the uteroplacental demarcation yielded an area under the ROC curve of 0.94 (95% CI, 0.86-1.00). Our proposed scoring system is highly predictive of MAP in patients at risk. This allows an adequate multidisciplinary team approach for the planning and timing of delivery in such cases. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Adverse fetal outcome in road accidents: Injury mechanism study and injury criteria development in a pregnant woman finite element model

This study documents the development of adverse fetal outcome predictors dedicated to the analysis of road accidents involving pregnant women. To do so, a pre-existing whole body finite element model representative of a 50th percentile 26 weeks pregnant woman was used. A total of 8 accident scenarios were simulated with the model positioned on a sled. Each of these scenarios was associated to a risk of adverse fetal outcome based on results from real car crash investigations involving pregnant women from the literature. The use of airbags and accidents involving unbelted occupants were not considered in this study. Several adverse fetal outcome potential predictors were then evaluated with regard to their correlation to this risk of fetal injuries. Three predictors appeared strongly correlated to the risk of adverse fetal outcome: (1) the intra uterine pressure at the placenta fetal side area (r=0.92), (2) the fetal head acceleration (HIC) (r=0.99) and (3) area of utero-placental interface over a strain threshold (r=0.90). Finally, sensitivity analysis against slight variations of the simulation parameters was performed and assess robustness of these criteria.

The effect of including a fetus in the uterus model on the risk of fetus mortality through drop test and frontal crash simulations

ABSTRACTComputational modelling is an effective way of estimating the risk of injuries and fatalities in road traffic accidents. Computational pregnant occupant modelling has an additional important role in the investigation of the risk of fetus mortality in crash test simulations. In this paper, the effect of including the fetus in the uterus of the pregnant occupant model is investigated. First, isolated drop test simulations with the uterus of the computational pregnant occupant model, ‘Expecting’, with and without a fetus are used to show the effect of the presence of fetus in the uterus model. Then ‘Expecting’ with and without the fetus is used with varying levels of restraint system use, such as fully restrained, ‘seatbelt only’, ‘airbag only’ and ‘no restraint’, in frontal crash simulations, representing five levels of impacts. Maximum strains developed in the uteroplacental interface with and without a fetus are compared in every case. Both simulations predict higher risks of placental abruption when the fetus is included in the model. Simulations with and without a fetus model show that inclusion of a 38-week fetus model causes higher strains in the placental region of uterus.

Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus--harvesting the power of omic technology, biomarkers and in vitro or in vivo models to facilitate the treatment of thrombosis.

Maternal thromboembolism and a spectrum of placenta-mediated complications including the pre-eclampsia syndromes, fetal growth restriction, fetal loss, and abruption manifest a shared etiopathogenesis and predisposing risk factors. Furthermore, these maternal and fetal complications are often linked to subsequent maternal health consequences that comprise the metabolic syndrome, namely, thromboembolism, chronic hypertension, and type II diabetes. Traditionally, several lines of evidence have linked vasoconstriction, excessive thrombosis and inflammation, and impaired trophoblast invasion at the uteroplacental interface as hallmark features of the placental complications. "Omic" technologies and biomarker development have been largely based upon advances in vascular biology, improved understanding of the molecular basis and biochemical pathways responsible for the clinically relevant diseases, and increasingly robust large cohort and/or registry based studies. Advances in understanding of innate and adaptive immunity appear to play an important role in several pregnancy complications. Strategies aimed at improving prediction of these pregnancy complications are often incorporating hemodynamic blood flow data using non-invasive imaging technologies of the utero-placental and maternal circulations early in pregnancy. Some evidence suggests that a multiple marker approach will yield the best performing prediction tools, which may then in turn offer the possibility of early intervention to prevent or ameliorate these pregnancy complications. Prediction of maternal cardiovascular and non-cardiovascular consequences following pregnancy represents an important area of future research, which may have significant public health consequences not only for cardiovascular disease, but also for a variety of other disorders, such as autoimmune and neurodegenerative diseases.

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Natural killer (NK) cells play an important role in the establishment/maintenance of normal pregnancy (NL), as well as in preeclampsia (PE). NK cells make up 5–10% of peripheral leukocytes, but comprise >70% at the uteroplacental interface. They regulate trophoblast invasion and alter the T helper 1/2 cytokine balance in NL and PE. Natural cytotoxicity receptors (NCR) are unique to the NK cell surface and lead to direct cytotoxicity as well as indirect inflammatory pathways via secreted cytokines and angiogenic factors. Acute PE has been associated with decreased expression of NCR1/NKp46 compared with NL. DNA methylation in CpGs at transcription start sites (TSS) can be inversely correlated with gene transcription. We characterized methylation patterns in the NCR1 gene in NL and PE. The methylation profile of 2 CpG sites in the NCR1 gene was analyzed in leukocyte DNA in a discovery cross-sectional cohort of 14 NL + 14 PE at delivery (D) and in a longitudinal replication cohort of 17NL + 6 PE (D v. postpartum (PP)). Genomic DNA was derived from buffy coat, bisulfite modified, then run on an Illumina Methylation Assay. Mean methylation levels at each CpG site were compared using an appropriate t-test. One of the two CpG sites at the TSS showed significant methylation differences in PE versus NL controls at the time of D (0.53 v. 0.47; absolute difference of 6%; p < 0.018) and at NL-D compared with NL-PP (p < 0.001) but not PE-D versus PE-PP. Our results suggest that the changes in NCR1 expression and ultimately NK functionality that are associated with NL pregnancy yet altered in PE may be controlled by epigenetic mechanisms. W.M. White: None. K. Borowski: None. B. Brost: None. N. Davies: None. C. Rose: None. Z. Sun: None. T. Weissgerber: None. V.D. Garovic: None.

Highly significant association between two common single nucleotide polymorphisms in CORIN gene and preeclampsia in Caucasian women.

Preeclampsia is a frequent medical complication during pregnancy. Corin, a serine protease which activates pro-atrial natriuretic peptide, has recently been shown to be involved in the pathophysiology of preeclampsia. The aim of this study was to search for CORIN gene variations and their association to preeclampsia in Caucasian and African women. Our study population was composed of 571 pregnant women (295 with preeclampsia and 276 normotensive controls) matched for maternal and gestational age, and ethnic origin. The 22 exons of the CORIN gene were sequenced in a discovery sample (n = 260), where 31 single nucleotide polymorphisms were identified. In a replication sample (n = 311), 4 single nucleotide polymorphisms were tested. Two minor alleles (C for rs2271036 and G for rs2271037) were significantly associated to preeclampsia. Adjusted odds ratios [95% confidence interval] were 2.5 [1.2–3.8] (p = 0.007) and 2.3 [1.5–3.5] (p = 1.3×10−4), respectively. These associations were ethnic-specific, as only found in the Caucasian of subjects (odds ratio = 3.5 [1.8–6.6], p = 1.1×10−4; odds ratio = 3.1 [1.7–5.8], p = 2.1×10−4, for each single nucleotide polymorphism, respectively). The two single nucleotide polymorphisms are in almost perfect linkage disequilibrium (r2 = 0.93). No specific association was found with severe preeclampsia, early-onset preeclampsia nor fetal growth retardation. In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. Our findings further support the probability of a critical role of corin in preeclamspia pathophysiology at the uteroplacental interface.