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The article discusses the COLLECT database, developed to provide researchers with a platform to collect data related to the fields of pregnancy and placental research. Topics include factors that contribute to the slow down of the development of new treatments and preventive strategies on the pathopysiology of obstetric syndromes, the importance of collaboration and data sharing in addressing the barriers of research, and the Global Pregnancy Collaboration (CoLab).

There is evidence for both endothelial cell and peripheral blood leukocyte (PBL) activation in pre-eclampsia. Syncytiotrophoblast microvillous membranes (STBM) are shed in greater quantities from the placenta in pre-eclampsia, disrupt cultured endothelial cells in vitro and may be the immediate cause of the maternal syndrome. The aim of this study was to determine if endothelial cells co-cultured with STBM release factors that can activate PBL in vitro. Flow cytometry was used to measure changes in intracellular free ionized calcium ([Ca2+]i), pH (pHi) and reactive oxygen species (iROS) as indices of leukocyte activation. PBL from male non-pregnant donors was exposed to supernatants from human umbilical vein endothelial cells (HUVEC) cultured with STBM. The time course of changes in [Ca2+]i, pHi and iROS was determined and compared with appropriate control measurements. The test supernatants caused significant activation of granulocytes and monocytes in terms of increases in [Ca2+]i and falls in pHi and release of iROS. Lymphocytes responded only with respect to increases in iROS. The results define a possible mechanism for the activation of PBL in pre-eclampsia, as being secondary to endothelial cell activation caused by circulating STBM shed in excess amounts from the placenta. [ABSTRACT FROM AUTHOR]

Background: Increasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low "proangiogenic" placental growth factor concentrations and increased "antiangiogenic" soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome., Objective: This study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low "proangiogenic" placental growth factor levels, increased "antiangiogenic" soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1-placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome., Study Design: This was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37 +0 ), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups-the "complicated" group (n=32) and the "uncomplicated" group (n=924)-according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results., Results: Mean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P =.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start ( r s =-0.068; 95% confidence interval, -0.131 to -0.004; P =.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end ( r s =-0.068; 95% confidence interval, -0.131 to -0.005; P =.036), and high soluble fms-like tyrosine kinase-1-placental growth factor ratio and low short-term variation end ( r s =-0.071; 95% confidence interval, -0.134 to -0.008; P =.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the "complicated" compared with the "uncomplicated" group (0% to 17% vs 4% to 8%)., Conclusion: More automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile (lower placental growth factor) increased the rates of alerts more rapidly in pregnancies with adverse neonatal outcome compared with those without. We suggest that future studies developing and testing prediction tools for intrapartum fetal compromise include predelivery maternal placental growth factor measurements., (© 2022 The Authors.)

Preeclampsia evolves in 2 stages: a placental problem that generates signals to the mother to cause a range of responses that comprise the second stage (preeclampsia syndrome). The first stage of early-onset preeclampsia is poor placentation, which we here call malplacentation. The spiral arteries are incompletely remodeled, leading to later placental malperfusion, relatively early in the second half of pregnancy. The long duration of the first stage (several months) is unsurprisingly associated with fetal growth restriction. The first stage of late-onset preeclampsia, approximately 80% of total cases, is shorter (several weeks) and part of a process that is common to all pregnancies. Placental function declines as it outgrows uterine capacity, with increasing chorionic villous packing, compression of the intervillous space, and fetal hypoxia, and causes late-onset clinical presentations such as "unexplained" stillbirths, late-onset fetal growth restriction, or preeclampsia. The second stages of early- and late-onset preeclampsia share syncytiotrophoblast stress as the most relevant feature that causes the maternal syndrome. Syncytiotrophoblast stress signals in the maternal circulation are probably the most specific biomarkers for preeclampsia. In addition, soluble fms-like tyrosine kinase-1 (mainly produced by syncytiotrophoblast) is the best-known biomarker and is routinely used in clinical practice in many locations. How the stress signals change over time in normal pregnancies indicates that syncytiotrophoblast stress begins on average at 30 to 32 weeks' gestation and progresses to term. At term, syncytiotrophoblast shows increasing markers of stress, including apoptosis, pyroptosis, autophagy, syncytial knots, and necrosis. We label this phenotype the "twilight placenta" and argue that it accounts for the clinical problems of postmature pregnancies. Senescence as a stress response differs in multinuclear syncytiotrophoblast from that of mononuclear cells. Syncytiotrophoblast irreversibly acquires part of the senescence phenotype (cell cycle arrest) when it is formed by cell fusion. The 2 pathways converge on the common pathologic endpoint, syncytiotrophoblast stress, and contribute to preeclampsia subtypes. We highlight that the well-known heterogeneity of the preeclampsia syndrome arises from different pathways to this common endpoint, influenced by maternal genetics, epigenetics, lifestyle, and environmental factors with different fetal and maternal responses to the ensuing insults. This complexity mandates a reassessment of our approach to predicting and preventing preeclampsia, and we summarize research priorities to maximize what we can learn about these important issues., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Post-date pregnancies have an increased risk of adverse delivery outcome. Our aim was to explore the association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in clinically healthy post-date pregnancies., Material and Methods: Women with healthy singleton post-date pregnancies between 40 +2 and 42 +2  weeks of gestation were recruited to this prospective, observational study conducted at Oslo University Hospital, Norway (NCT03100084). Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the maternal serum samples closest to delivery. The composite adverse delivery outcome included fetal acidemia, low Apgar score (<4 at 1 min or <7 at 5 min), asphyxia, fetal death, assisted ventilation for more than 6 h, meconium aspiration, hypoxic-ischemic encephalopathy, therapeutic hypothermia, operative delivery due to fetal distress, or pathological placental histology findings. Two study-independent senior consultant obstetricians blinded to biomarker results concluded, based on clinical expert opinion, whether the adverse delivery outcomes were most likely associated with placental dysfunction ("likely placental cause") or not. Means were compared using one-way analysis of variance and Bonferroni corrected pairwise comparisons between groups. Receiver operating characteristic (ROC) curves assessed the predictive ability of PlGF, sFlt-1/PlGF ratio, and PlGF <10th centile after adjustment for gestational age at blood sampling., Results: Of 501 pregnancies reviewed for predefined adverse delivery outcomes and for a likely placental cause, 468 were healthy pregnancies and subsequently assigned to either the "uncomplicated" (no adverse outcome, n = 359), "intermediate" (non-placental cause/undetermined, n = 90), or "complicated" (likely placental cause, n = 19) group. There was a significant difference in mean PlGF and sFlt-1/PlGF ratio between the "complicated", "intermediate", and "uncomplicated" groups (108, 185, and 179 pg/mL, p = 0.001; and 48.3, 23.4, and 24.6, p = 0.002, respectively). There was a higher proportion of PlGF concentration <10th centile in the "complicated" group compared with the "intermediate" and "uncomplicated" groups (42.1% vs. 11.1% and 9.5%, p = 0.001). The largest area under the ROC curve for predicting "complicated" outcome was achieved by PlGF concentration and gestational age at blood sampling (0.76; 95% CI 0.65-0.86)., Conclusions: In clinically healthy post-date pregnancies, an antiangiogenic pre-delivery profile (lower PlGF level and higher sFlt-1/PlGF ratio) was associated with composite adverse delivery outcome of a likely placental cause., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

HLA-G, a non-classical HLA molecule expressed by extravillous trophoblasts, plays a role in the maternal immune tolerance towards fetal cells. HLA-G expression is regulated by genetic polymorphisms in the 3' untranslated region (3'UTR). Low levels of HLA-G in the maternal circulation and placental tissue are linked to preeclampsia. Our objective was to investigate whether variants of the 3'UTR of the HLA-G gene in mother and fetus are associated with acute atherosis, a pregnancy specific arterial lesion of the decidua basalis that is prevalent in preeclampsia. Paired maternal and fetal DNA samples from 83 normotensive and 83 preeclamptic pregnancies were analyzed. We sequenced the part of the HLA-G 3'UTR containing a 14-bp insertion/deletion region and seven single nucleotide polymorphisms (SNPs). Associations with acute atherosis were tested by logistic regression. The frequency of heterozygosity for the 14-bp polymorphism (Ins/Del) and the +3142 SNP (C/G) variant in the fetus are associated with acute atherosis in preeclampsia (66.7 % vs. 39.6 %, p = 0.039, and 69.0 % vs. 43.4 %, p = 0.024). Furthermore, the fetal UTR-3 haplotype, which encompasses the 14-bp deletion and the +3142G variant, is associated with acute atherosis in preeclampsia (15 % vs. 3.8 %, p = 0.016). In conclusion, HLA-G polymorphisms in the fetus are associated with acute atherosis. We hypothesize that these polymorphisms lead to altered HLA-G expression in the decidua basalis, affecting local feto-maternal immune tolerance and development of acute atherosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Uteroplacental acute atherosis (AA) is a common spiral arterial lesion in preeclampsia, characterized by intramural foam cells, fibrinoid necrosis, and a perivascular immune cell infiltrate. A clear definition of this infiltrate is lacking. Therefore, our aim was to characterize lymphocytes in pre-defined zones regarding spiral arteries with or without AA, from preeclamptic and normotensive pregnancies. Lymphocytes were characterized in decidua basalis samples (n = 91), previously evaluated for AA, around spiral arteries in three pre-defined zones; 1) intramural, 2) perivascular and 3) interstitial. Adjacent serial sections were immunostained to identify different T-cell populations (CD3+, CD8+, FOXP3+), and NK-cells (CD56+). CD3+CD8- T-cells were also identified. These were presumed to be largely CD4+ T-cells. AA was associated with significantly higher intramural CD3+ cell concentrations in Zone 1, in both normotensives and preeclamptics. In preeclamptics only, this difference extended into Zone 2. Similar results were observed for CD3+CD8- cells. AA was also associated with increased intramural CD8+ concentration; however, the number of cells was low. Regulatory T-cells (FOXP3+) were generally scarce or absent in all pre-defined zones. Although intramural NK-cells (CD56+) were scarce, the intramural concentration was significantly lower in spiral arteries with AA compared to without AA in preeclamptics. Our main finding was that CD3+CD8-FoxP3- T-cells were associated with AA. We therefore suggest that T-cells, of a non-regulatory CD4+ subtype, could be involved in the formation of spiral artery AA in the decidua basalis. Whether AA gives rise to, or is partly mediated by increased T-cell concentration around the lesions, remains to be determined., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral arteries in the decidua basalis layer of the pregnant uterus. This layer forms the fetal-maternal immunological interface, where fetal extravillous trophoblasts interact with maternal immune cells to promote decidual spiral artery remodeling and maternal immune tolerance towards the fetus. Of the classical polymorphic class I HLAs, extravillous trophoblasts express only HLA-C. HLA-C is a ligand for killer immunoglobulin-like receptors (KIR) on NK- and T-cells. Genetic combinations of fetal HLA-C and maternal KIRs affect pregnancy outcome. However, the role of HLA and KIR genes in acute atherosis is unknown. We hypothesized that specific genetic combinations of fetal HLA and maternal KIR are associated with the presence of acute atherosis lesions in the decidua basalis. We genotyped HLA class-I and II loci in paired fetal and maternal DNA samples from 166 pregnancies (83 preeclamptics, 83 controls). Acute atherosis was identified in 38 of these. Maternal KIR-loci were also genotyped. We found that the combination of maternal KIR-B haplotype and fetal HLA-C2 was significantly associated with acute atherosis in preeclampsia. In preeclamptic pregnancies with acute atherosis, 60% had this combination, compared to 24.5% in those without acute atherosis (p = 0.001). We suggest that interactions between fetal HLA-C2 and activating KIRs on maternal decidual NK-cells or T-cells may contribute to the formation of acute atherosis by promoting local decidual vascular inflammation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Uteroplacental acute atherosis (AA) is a pregnancy-specific arterial lesion resembling early stages of atherosclerosis. AA is frequent in preeclamptic pregnancies, which associate with increased long-term maternal risk of atherosclerotic cardiovascular disease. We hypothesized that AA in pregnant women associates with classical risk factors for cardiovascular disease, including hypertension, hyperlipidemia, glucose intolerance, elevated C-reactive protein, age, and body mass index. We included 237 women delivered by cesarean section (healthy pregnancies, n=94; preeclampsia, n=87; pregestational and gestational diabetes mellitus, n=39; diabetes mellitus with preeclampsia, n=17). They provided blood before delivery for biomarker analyses. AA was diagnosed by immunohistochemistry in uteroplacental (decidual) tissue collected after placental removal. Statistical analyses were performed with Mann-Whitney test. Levels of traditional cardiovascular markers were not associated with decidual AA within the groups of women with normotensive pregnancies, preeclampsia, diabetes mellitus, or diabetes mellitus superimposed with preeclampsia. However, the oldest patient age quartile (36-43 years old) with AA had significantly higher levels of LDL (low-density lipoprotein) and apolipoprotein B (both P<0.01) than women of the same age without AA. AA was associated with elevated median prepregnancy/early pregnancy systolic blood pressure ( P=0.01) in the total cohort, but as preeclampsia was strongly associated with this finding ( P<0.01), this was likely caused by a large proportion of preeclamptic pregnancies in the AA group (62.7%). Our findings demonstrate that dyslipidemia associated with cardiovascular risk is a feature of uteroplacental AA in older women, not of AA in pregnancy in general.

Objective: To evaluate the test performance of 47 biomarkers and ultrasound parameters for the prediction of delivery of a small-for-gestational-age (SGA) infant and adverse perinatal outcome in women presenting with suspected pre-eclampsia., Methods: This was a prospective, multicenter observational study in which 47 biomarkers and ultrasound parameters were measured in 397 women with a singleton pregnancy presenting with suspected preterm pre-eclampsia between 20 + 0 and 36 + 6 weeks' gestation, with the objective of evaluating them as predictors of subsequent delivery of a SGA infant and adverse perinatal outcome. Women with confirmed pre-eclampsia at enrollment were excluded. Factor analysis and stepwise logistic regression were performed in two prespecified groups stratified according to gestational age at enrollment. The primary outcome was delivery of a SGA infant with a birth weight < 3 rd customized centile (SGA-3), and secondary outcomes were a SGA infant with a birth weight < 10 th customized centile and adverse perinatal outcome., Results: In 274 women presenting at 20 + 0 to 34 + 6 weeks' gestation, 96 (35%) delivered a SGA-3 infant. For prediction of SGA-3, low maternal placental growth factor (PlGF) concentration had a sensitivity of 93% (95% CI, 84-98%) and negative predictive value (NPV) of 90% (95% CI, 76-97%) compared with a sensitivity of 71% (95% CI, 58-82%) and a NPV of 79% (95% CI, 68-87%) for ultrasound parameters (estimated fetal weight or abdominal circumference < 10 th centile). No individual biomarker evaluated had a better performance than did PlGF, and marker combinations made only small improvements to the test performance. Similar results were found in 123 women presenting between 35 + 0 and 36 + 6 weeks' gestation., Conclusion: In women presenting with suspected preterm pre-eclampsia, measurement of PlGF offers a useful adjunct for identifying those at high risk of delivering a SGA infant, allowing appropriate surveillance and timely intervention. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Cost and availability of a database often impede research while the lack of compatibility inhibits collaboration by making merging of databases difficult or impossible. The Global Pregnancy Collaboration (CoLab) has promoted harmonization of studies and standardized data collection to facilitate pregnancy and placental research. Its online database, COLLECT, allows collection of minimal and optimal clinical datasets to accompany basic and applied science studies and provides a placental sample inventory system. COLLECT is available free of charge in LMIC and for $100 per month in HIC. Data is the property of the investigator but with permission can be combined into larger studies across centers and countries., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Continuous intrapartum fetal monitoring remains a significant clinical challenge. We propose using cohorts of routinely collected data. We aim to combine non-classical (data-driven) and classical cardiotocography features with clinical features into a system (OxSys), which generates automated alarms for the fetus at risk of intrapartum hypoxia. We hypothesize that OxSys can outperform clinical diagnosis of "fetal distress", when optimized and tested over large retrospective data sets., Material and Methods: We studied a cohort of 22 790 women in labor (≥36 weeks of gestation). Paired umbilical blood analyses were available. Perinatal outcomes were defined by objective criteria (normal; severe, moderate or mild compromise). We used the data retrospectively to develop a prototype of OxSys, by relating its alarms to perinatal outcome, and comparing its performance against standards achieved by bedside diagnosis., Results: OxSys1.5 triggers an alarm if the initial trace is nonreactive or the decelerative capacity (a nonclassical cardiotocography feature), exceeds a threshold, adjusted for preeclampsia and thick meconium. There were 187 newborns with severe, 613 with moderate and 3197 with mild compromise; and 18 793 with normal outcome. OxSys1.5 increased the sensitivity for compromise detection: 43.3% vs. 38.0% for severe (p = 0.3) and 36.1% vs. 31.0% for moderate (p = 0.06); and reduced the false-positive rate (14.4% vs. 16.3%, p < 0.001)., Conclusions: Large historic cohorts can be used to develop and optimize computerized cardiotocography monitoring, combining clinical and cardiotocography risk factors. Our simple prototype has demonstrated the principle of using such data to trigger alarms, and compares well with clinical judgment., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To evaluate 47 biomarkers (selected from the current medical literature), in isolation or in combination with placental growth factor (PlGF), to determine the need for delivery within 14 days, in women presenting with suspected preterm preeclampsia., Methods: In a prospective, multicenter observational study, 47 biomarkers were measured in 423 women presenting with suspected preterm preeclampsia (in two prespecified groups: group 1 at less than 35 weeks of gestation and group 2 presenting between 35 0/7 and 36 6/7 weeks of gestation) to evaluate their ability to determine the primary endpoint: preeclampsia requiring delivery within 14 days. Using factor analysis and stepwise logistic regression, we sought one or more additional biomarkers for optimal determination of the primary endpoint., Results: In women presenting at less than 35 weeks of gestation (n=286), the best performing combination of PlGF, podocalyxin, endoglin, procalcitonin (receiver operating curve [ROC] area 0.90, 95% confidence interval [CI] 0.86-0.93) was not statistically better than PlGF alone (ROC 0.87, 95% CI 0.83-0.92; P=.43) for preeclampsia requiring delivery within 14 days. Two other single markers had test performance that was not significantly different to PlGF (soluble fms-like tyrosine kinase-1 [sFlt-1] ROC 0.83, 95% CI 0.78-0.88; endoglin ROC 0.83, 95% CI 0.79-0.88). Similar findings were found in women presenting between 35 0/7 and 36 6/7 weeks of gestation (n=137): ROC for PlGF alone 0.75 (95% CI 0.67-0.83); ROC for PlGF, cystatin, pregnancy-associated plasma protein A in combination 0.81 (95% CI 0.74-0.88; P=.40)., Conclusion: This study supports the growing body of evidence that a single angiogenesis-related biomarker (PlGF, sFlt-1, or endoglin) alone represents a useful diagnostic test for women presenting with suspected preterm preeclampsia.

Acute atherosis (Aa) affects uteroplacental spiral arteries in 20-40% of cases of preeclampsia. Its hallmark is lipid-filled, CD68-positive foam cells. It usually develops in the decidua (the pregnancy endometrium) at the distal ends of arteries that are often unremodelled in their proximal segments. Aa resembles the early stages of atherosclerosis, which becomes symptomatic in the middle-aged and elderly, in contrast to the young age of pregnant women with Aa. Although the mechanisms of Aa are largely unknown, they are likely to resemble those of early atherosclerosis, which is an inflammatory lesion of the arterial wall. However, Aa is likely to have added pregnancy-specific features. Because it also occurs in normotensive pregnancies, complicated by foetal growth restriction, diabetes mellitus or autoimmune disease or even without any complications, we suggest that Aa is the final manifestation of several inflammatory processes. We revisit an old proposition that immunological incompatibility between mother and foetus may sometimes induce Aa. We propose that excessive inflammatory activation, of other aetiologies, primarily in the decidua basalis, may explain the different ways in which Aa occurs. We speculate that the subset of women who develop these lesions may be at an increased risk of atherosclerotic arterial disease later in life. We hypothesise that use of anti-atherogenic statins during established preeclampsia may ameliorate Aa, improve uteroplacental perfusion and enhance pregnancy outcome., (Copyright © 2013. Published by Elsevier Ireland Ltd.)