Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns.

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.

Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways.

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.

The association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in healthy post-date pregnancies.

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.

A possible role for HLA-G in development of uteroplacental acute atherosis in preeclampsia.

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.

Computer-based intrapartum fetal monitoring and beyond: A review of the 2nd Workshop on Signal Processing and Monitoring in Labor (October 2017, Oxford, UK).

The second Signal Processing and Monitoring in Labor workshop gathered researchers who utilize promising new research strategies and initiatives to tackle the challenges of intrapartum fetal monitoring. The workshop included a series of lectures and discussions focusing on: new algorithms and techniques for cardiotocogoraphy (CTG) and electrocardiogram acquisition and analyses; the results of a CTG evaluation challenge comparing state-of-the-art computerized methods and visual interpretation for the detection of arterial cord pH <7.05 at birth; the lack of consensus about the role of intrapartum acidemia in the etiology of fetal brain injury; the differences between methods for CTG analysis "mimicking" expert clinicians and those derived from "data-driven" analyses; a critical review of the results from two randomized controlled trials testing the former in clinical practice; and relevant insights from modern physiology-based studies. We concluded that the automated algorithms performed comparably to each other and to clinical assessment of the CTG. However, the sensitivity and specificity urgently need to be improved (both computerized and visual assessment). Data-driven CTG evaluation requires further work with large multicenter datasets based on well-defined labor outcomes. And before first tests in the clinic, there are important lessons to be learnt from clinical trials that tested automated algorithms mimicking expert CTG interpretation. In addition, transabdominal fetal electrocardiogram monitoring provides reliable CTG traces and variability estimates; and fetal electrocardiogram waveform analysis is subject to promising new research. There is a clear need for close collaboration between computing and clinical experts. We believe that progress will be possible with multidisciplinary collaborative research.

Classical Cardiovascular Risk Markers in Pregnancy and Associations to Uteroplacental Acute Atherosis.

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.

The combination of maternal KIR-B and fetal HLA-C2 is associated with decidua basalis acute atherosis in pregnancies with preeclampsia.

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.

Availability of COLLECT, a database for pregnancy and placental research studies worldwide.

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.

Computerized data-driven interpretation of the intrapartum cardiotocogram: a cohort study.

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.

Diagnostic Biomarkers in Women With Suspected Preeclampsia in a Prospective Multicenter Study.

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.

Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms.

BACKGROUND: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. METHODS: Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. RESULTS: Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves. CONCLUSIONS: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes.

No effect of modest selenium supplementation on insulin resistance in UK pregnant women, as assessed by plasma adiponectin concentration.

Concern has been expressed recently that Se may increase the risk of type 2 diabetes, but this has not been tested in a randomised-controlled trial (RCT) in pregnant women. We took advantage of having stored plasma samples from the Se in Pregnancy Intervention (SPRINT) RCT of Se supplementation in pregnancy to test the effect of Se supplementation on a marker of insulin resistance in UK pregnant women. Because our blood samples were not fasted, we measured plasma adiponectin concentration, a recognised marker of insulin resistance that gives valid measurements in non-fasted samples, as diurnal variability is minor and there is no noticeable effect of food intake. In SPRINT, 230 primiparous UK women were randomised to treatment with Se (60 µg/d) or placebo from 12 weeks of gestation until delivery. We hypothesised that supplementation with Se at a nutritional level would not exacerbate the fall in adiponectin concentration that occurs in normal pregnancy, indicating the lack of an adverse effect on insulin resistance. Indeed, there was no significant difference between the two groups in the change in adiponectin from 12 to 35 weeks (P=0·938), nor when the analysis was restricted to the bottom or top quartiles of baseline whole-blood Se (P=0·515 and 0·858, respectively). Cross-sectionally, adiponectin concentration was not associated with any parameter of Se status, either at 12 or 35 weeks. It is reassuring that a nutritional dose of Se had no adverse effect on the concentration of adiponectin, a biomarker of insulin resistance, in pregnant women of modest Se status.

Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency.

PURPOSE: Selenium is an essential trace mineral and a component of selenoproteins that are involved in the production of thyroid hormones and in regulating the immune response. We aimed to explore the effect of low-dose selenium supplementation on thyroid peroxidase antibody (TPO-Ab) concentration and thyroid function in pregnant women from a mild-to-moderate iodine-deficient population. METHODS: Samples and data were from a secondary analysis of Selenium in PRegnancy INTervention (SPRINT), a double-blind, randomized, placebo-controlled study that recruited 230 women with singleton pregnancies from a UK antenatal clinic at 12 weeks of gestation. Women were randomized to receive 60 µg/day selenium or placebo until delivery. Serum thyroid peroxidase antibodies (TPO-Ab), thyrotropin (TSH) and free thyroxine (FT4) were measured at 12, 20 and 35 weeks and thyroglobulin antibodies (Tg-Ab) at 12 weeks. RESULTS: 93.5% of participants completed the study. Se supplementation had no more effect than placebo in decreasing TPO-Ab concentration or the prevalence of TPO-Ab positivity during the course of pregnancy. In women who were either TPO-Ab or Tg-Ab negative at baseline (Thy-Ab(-ve)), TSH increased and FT4 decreased significantly throughout gestation (P < 0.001), with no difference between treatment groups. In women who were Thy-Ab(+ve) at baseline, TSH tended to decrease and was lower than placebo at 35 weeks (P = 0.050). FT4 fell more on Se than placebo supplementation and was significantly lower at 35 weeks (P = 0.029). CONCLUSIONS: Low-dose selenium supplementation in pregnant women with mild-to-moderate deficiency had no effect on TPO-Ab concentration, but tended to change thyroid function in Thy-Ab(+ve) women.

Acute atherosis in vacuum suction biopsies of decidua basalis: An evidence based research definition.

BACKGROUND: Acute atherosis (AA) of the uteroplacental spiral arteries has been characterised by subendothelial lipid-laden foam cells, perivascular leukocyte infiltrates (PVI) and fibrinoid necrosis. Because precise diagnostic criteria are not available for comparative research studies we developed and tested new simplified criteria based on 237 cases. METHODS: Decidual basalis samples were collected by vacuum suction at elective cesarean deliveries. Spiral arteries were evaluated in serial decidual tissue sections from women with normal pregnancy, preeclampsia, and diabetes. Features of AA were sought in parallel sections stained with H&E and immunostained for CD68, cytokeratin CK7 and desmin, and costained with Periodic Acid Schiff (PAS). RESULTS: Foam cell lesions were defined as two or more adjacent, intramural, vacuolated CD68 positive cells, PVI as a focal perivascular lymphocyte accumulation, more dense than in the surrounding decidua. Increased fibrinoid (PAS positive) was identified if present in ≥75% of the arterial wall circumference. PVI and increased fibrinoid were significantly associated with preeclampsia but not specifically associated with the presence of foam cell lesions. Hence we diagnosed decidua basalis AA lesions solely by the presence of foam cell lesions, occurring in preeclampsia (37%), diabetes (10%) and healthy normotensive women (11%). The simplified criterion was reproducible by different investigators. Decidua basalis AA occurred most commonly and extensively in preeclampsia, but did not distinguish between preterm and term disease. DISCUSSION: Our evidence based criterion for decidua basalis AA diagnosis in vacuum suction biopsies may not apply to myometrial or decidua parietalis arteries. In decidual basalis samples it should facilitate comparisons between research studies, to improve pathophysiological understanding of AA and preeclampsia.

Genetic polymorphisms that affect selenium status and response to selenium supplementation in United Kingdom pregnant women.

BACKGROUND: Low selenium status in pregnancy has been associated with a number of adverse conditions. In nonpregnant populations, the selenium status or response to supplementation has been associated with polymorphisms in dimethylglycine dehydrogenase (DMGDH), selenoprotein P (SEPP1) and the glutathione peroxidases [cytosolic glutathione peroxidase (GPx1) and phospholipid glutathione peroxidase (GPx4)]. OBJECTIVE: We hypothesized that, in pregnant women, these candidate polymorphisms would be associated with selenium status in early pregnancy, its longitudinal change, and the interindividual response to selenium supplementation at 60 µg/d. DESIGN: With the use of stored samples and data from the United Kingdom Selenium in Pregnancy Intervention (SPRINT) study in 227 pregnant women, we carried out genetic-association studies, testing for associations between selenium status, its longitudinal change, and response to supplementation and common genetic variation in DMGDH (rs921943), SEPP1 (rs3877899 and rs7579), GPx1 (rs1050450) and GPx4 (rs713041). Selenium status was represented by the concentration of whole-blood selenium at 12 and 35 wk of gestation, the concentration of toenail selenium at 16 wk of gestation, and plasma glutathione peroxidase (GPx3) activity at 12 and 35 wk of gestation. RESULTS: Our results showed that DMGDH rs921943 was significantly associated with the whole-blood selenium concentration at 12 wk of gestation (P = 0.032), which explained ≤2.0% of the variance. This association was replicated with the use of toenail selenium (P = 0.043). In unsupplemented women, SEPP1 rs3877899 was significantly associated with the percentage change in whole-blood selenium from 12 to 35 wk of gestation (P = 0.005), which explained 8% of the variance. In supplemented women, SEPP1 rs3877899 was significantly associated with the percentage change in GPx3 activity from 12 to 35 wk of gestation (P = 0.01), which explained 5.3% of the variance. Selenium status was not associated with GPx1, GPx4, or SEPP1 rs7579. CONCLUSIONS: In agreement with previous studies, we show that the genetic variant rs921943 in DMGDH is significantly associated with selenium status in United Kingdom pregnant women. Notably, our study shows that women who carry the SEPP1 rs3877899 A allele are better able to maintain selenium status during pregnancy, and their GPx3 activity increases more with supplementation, which suggests better protection from low selenium status. The SPRINT study was registered at www.isrctn.com as ISRCTN37927591.

Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.

The maternal syndrome of preeclampsia is mediated by dysfunctional syncytiotrophoblast (STB). When this is stressed by uteroplacental malperfusion, its signaling to the mother changes, as part of a highly coordinated stress response. The STB signals are both proinflammatory and dysangiogenic such that the preeclamptic mother has a stronger vascular inflammatory response than normal, with an antiangiogenic bias. Angiogenic factors have limitations as preeclampsia biomarkers, especially for prediction and diagnosis of preeclampsia at term. However, if they are recognized as markers of STB stress, their physiological changes at term demonstrate that STB stress develops in all pregnancies. The biomarkers reveal that the duration of pregnancies is restricted by placental capacity, such that there is increasing placental dysfunction, at and beyond term. This capacity includes limitations imposed by the size of the uterus, the capacity of the uteroplacental circulation and, possibly, the supply of villous progenitor trophoblast cells. Limited placental capacity explains the increasing risks of postmaturity, including preeclampsia. Early-onset preeclampsia is predictable because STB stress and changes in its biomarkers are intrinsic to poor placentation, an early pregnancy pathology. Prediction of preeclampsia at term is not good because there is no early STB pathology. Moreover, biomarkers cannot accurately diagnose term preeclampsia against a background of universal STB dysfunction, which may or may not be clinically revealed before spontaneous or induced delivery. In this sense, postterm pregnancy is, at best, a pseudonormal state. However, the markers may prove useful in screening for women with more severe problems of postmaturity.