Actions of Esomeprazole on the Maternal Vasculature in Lean and Obese Pregnant Mice with Impaired Nitric Oxide Synthesis: A Model of Preeclampsia.

Preeclampsia is a devastating, multisystem disorder of pregnancy. It has no cure except delivery, which if premature can impart significant neonatal morbidity. Efforts to repurpose pregnancy-safe therapeutics for the treatment of preeclampsia have led to the assessment of the proton pump inhibitor, esomeprazole. Preclinically, esomeprazole reduced placental secretion of anti-angiogenic sFlt-1, improved endothelial dysfunction, promoted vasorelaxation, and reduced maternal hypertension in a mouse model. Our understanding of the precise mechanisms through which esomeprazole works to reduce endothelial dysfunction and enhance vasoreactivity is limited. Evidence from earlier studies suggested esomeprazole might work via the nitric oxide pathway, upregulating endothelial nitric oxide synthase (eNOS). Here, we investigated the effect of esomeprazole in a mouse model of L-NAME-induced hypertension (decreased eNOS activity). We further antagonised the model by addition of diet-induced obesity, which is relevant to both preeclampsia and the nitric oxide pathway. Esomeprazole did not decrease blood pressure in this model, nor were there any alterations in vasoreactivity or changes in foetal outcomes in lean mice. We observed similar findings in the obese mouse cohort, except esomeprazole treatment enhanced ex vivo acetylcholine-induced vasorelaxation. As acetylcholine induces nitric oxide production, these findings hint at a function for esomeprazole in the nitric oxide pathway.

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.

Rapid detection of fetal compromise using input length invariant deep learning on fetal heart rate signals.

Standard clinical practice to assess fetal well-being during labour utilises monitoring of the fetal heart rate (FHR) using cardiotocography. However, visual evaluation of FHR signals can result in subjective interpretations leading to inter and intra-observer disagreement. Therefore, recent studies have proposed deep-learning-based methods to interpret FHR signals and detect fetal compromise. These methods have typically focused on evaluating fixed-length FHR segments at the conclusion of labour, leaving little time for clinicians to intervene. In this study, we propose a novel FHR evaluation method using an input length invariant deep learning model (FHR-LINet) to progressively evaluate FHR as labour progresses and achieve rapid detection of fetal compromise. Using our FHR-LINet model, we obtained approximately 25% reduction in the time taken to detect fetal compromise compared to the state-of-the-art multimodal convolutional neural network while achieving 27.5%, 45.0%, 56.5% and 65.0% mean true positive rate at 5%, 10%, 15% and 20% false positive rate respectively. A diagnostic system based on our approach could potentially enable earlier intervention for fetal compromise and improve clinical outcomes.

The Effect of Fetal Heart Rate Segment Selection on Deep Learning Models for Fetal Compromise Detection.

Monitoring the fetal heart rate (FHR) is common practice in obstetric care to assess the risk of fetal compromise. Unfortunately, human interpretation of FHR recordings is subject to inter-observer variability with high false positive rates. To improve the performance of fetal compromise detection, deep learning methods have been proposed to automatically interpret FHR recordings. However, existing deep learning methods typically analyse a fixed-length segment of the FHR recording after removing signal gaps, where the influence of this segment selection process has not been comprehensively assessed. In this work, we develop a novel input length invariant deep learning model to determine the effect of FHR segment selection for detecting fetal compromise. Using this model, we perform five times repeated five-fold cross-validation on an open-access database of 552 FHR recordings and assess model performance for FHR segment lengths between 15 and 60 minutes. We show that the performance after removing signal gaps improves with increasing segment length from 15 minutes (AUC = 0.50) to 60 minutes (AUC = 0.74). Additionally, we demonstrate that using FHR segments without removing signal gaps achieves superior performance across signal lengths from 15 minutes (AUC = 0.68) to 60 minutes (AUC = 0.76). These results show that future works should carefully consider FHR segment selection and that removing signal gaps might contribute to the loss of valuable information.

Computerised Cardiotocography Analysis for the Automated Detection of Fetal Compromise during Labour: A Review.

The measurement and analysis of fetal heart rate (FHR) and uterine contraction (UC) patterns, known as cardiotocography (CTG), is a key technology for detecting fetal compromise during labour. This technology is commonly used by clinicians to make decisions on the mode of delivery to minimise adverse outcomes. A range of computerised CTG analysis techniques have been proposed to overcome the limitations of manual clinician interpretation. While these automated techniques can potentially improve patient outcomes, their adoption into clinical practice remains limited. This review provides an overview of current FHR and UC monitoring technologies, public and private CTG datasets, pre-processing steps, and classification algorithms used in automated approaches for fetal compromise detection. It aims to highlight challenges inhibiting the translation of automated CTG analysis methods from research to clinical application and provide recommendations to overcome them.

Plasma lipids are dysregulated preceding diagnosis of preeclampsia or delivery of a growth restricted infant.

BACKGROUND: Lipids serve as multifunctional metabolites that have important implications for the pregnant mother and developing fetus. Abnormalities in lipids have emerged as potential risk factors for pregnancy diseases, such as preeclampsia and fetal growth restriction. The aim of this study was to assess the potential of lipid metabolites for detection of late-onset preeclampsia and fetal growth restriction. METHODS: We used a case-cohort of 144 maternal plasma samples at 36 weeks' gestation from patients before the diagnosis of late-onset preeclampsia (n = 22), delivery of a fetal growth restricted infant (n = 55, defined as <5th birthweight centile), gestation-matched controls (n = 72). We performed liquid chromatography-tandem mass spectrometry (LC-QQQ) -based targeted lipidomics to identify 421 lipids, and fitted logistic regression models for each lipid, correcting for maternal age, BMI, smoking, and gestational diabetes. FINDINGS: Phosphatidylinositol 32:1 (AUC = 0.81) and cholesterol ester 17:1 (AUC = 0.71) best predicted the risk of developing preeclampsia or delivering a fetal growth restricted infant, respectively. Five times repeated five-fold cross validation demonstrated the lipids alone did not out-perform existing protein biomarkers, soluble tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) for the prediction of preeclampsia or fetal growth restriction. However, lipids combined with sFlt-1 and PlGF measurements improved disease prediction. INTERPRETATION: This study successfully identified 421 lipids in maternal plasma collected at 36 weeks' gestation from participants who later developed preeclampsia or delivered a fetal growth restricted infant. Our results suggest the predictive capacity of lipid measurements for gestational disorders holds the potential to improve non-invasive assessment of maternal and fetal health. FUNDING: This study was funded by a grant from National Health and Medical Research Council.

Circulating Chemerin Is Elevated in Women With Preeclampsia.

BACKGROUND: Preeclampsia is a severe complication of pregnancy. Chemerin is an adipokine secreted from adipose tissue and highly expressed in placenta. This study evaluated the biomarker potential of circulating chemerin to predict preeclampsia. METHODS: Maternal plasma and placenta were collected from women with early-onset preeclampsia (<34 weeks), with preeclampsia and eclampsia, or before preeclampsia diagnosis (36 weeks). Human trophoblast stem cells were differentiated into syncytiotrophoblast or extravillous trophoblasts across 96 hours. Cells were cultured in 1% O2 (hypoxia) or 5% O2 (normoxia). Chemerin was measured by enzyme-linked immunosorbent assay (ELISA) and RARRES2 (gene coding chemerin) by reverse transcription-quantitative polymerase chain reaction. RESULTS: Circulating chemerin was increased in 46 women with early-onset preeclampsia (<34 weeks) compared to 17 controls (P < .0006). Chemerin was increased in placenta from 43 women with early-onset preeclampsia compared to 24 controls (P < .0001). RARRES2 was reduced in placenta from 43 women with early-onset preeclampsia vs 24 controls (P < .0001). Chemerin was increased in plasma from 26 women with established preeclampsia (P = .006), vs 15 controls. Circulating chemerin was increased in 23 women who later developed preeclampsia vs 182 who did not (P = 3.23 × 10-6). RARRES2 was reduced in syncytiotrophoblast (P = .005) or extravillous trophoblasts (P < .0001). Hypoxia increased RARRES2 expression in syncytiotrophoblast (P = .01) but not cytotrophoblast cells. CONCLUSIONS: Circulating chemerin was elevated in women with early-onset preeclampsia, established preeclampsia, and preceding preeclampsia diagnosis of preeclampsia. RARRES2 was dysregulated in placenta complicated by preeclampsia and may be regulated through hypoxia. Chemerin may have potential as a biomarker for preeclampsia but would need to be combined with other biomarkers.

Management of late preterm preeclampsia: a comparison of maternal and fetal indications for delivery.

OBJECTIVE: To investigate delivery indications for women with late preterm preeclampsia and evaluate whether disease characteristics at presentation are predictive of delivery indication. METHODS: We conducted a retrospective case-control study at the Mercy Hospital for Women (a tertiary hospital in Melbourne, Australia). Indication for delivery was assessed among women presenting with preeclampsia between 30+0 and 36+0 weeks' gestation. Baseline maternal and disease characteristics, preeclampsia features at delivery and postnatal outcomes were compared between patients delivering for maternal, fetal, or for both maternal and fetal indications. RESULTS: 173 women were diagnosed with preeclampsia between 30+0 and 36+0 weeks' gestation. Maternal baseline characteristics were similar between the groups. We found that 55.5% of women were delivered on maternal grounds compared to 27.2% requiring delivery for fetal indications; and 17.3% for both maternal and fetal indications (p < .0001). At diagnosis, intrauterine growth restriction and abnormal Dopplers increased the risk of requiring delivery for fetal indications by 3.5 times and 2.4 times respectively. CONCLUSION: Women presenting with late preterm preeclampsia primarily required delivery for maternal disease progression rather than fetal compromise.

Growth trajectory of preterm small-for-gestational-age neonates.

AIM: To assess the growth trajectory of preterm small-for-gestational-age (SGA) neonates compared to preterm non-small-for-gestational age neonates in the neonatal intensive care unit and special care nursery. METHODS: We conducted a retrospective cohort study at a large tertiary hospital in Victoria, Australia, examining neonates ≤34 weeks' gestation admitted to the neonatal intensive care unit or special care nursery between 2013 and 2017. We categorized neonates according to their birth weight centile: <10th centile (small-for-gestational age) and ≥10th centile (non-small-for-gestational age). Growth trajectory was tracked based on serial weights obtained in the neonatal intensive care unit and special care nursery, using z-scores derived from Fenton preterm growth charts. Our primary outcome was the change in weight z-score from birth to discharge from neonatal intensive care unit or special care nursery. RESULTS: Of the 910 babies included, 88 were small-for-gestational age and 822 were appropriate-for gestational age. Both groups had a reduction in their weight z-score; however, SGA babies had a significantly smaller reduction (-0.62 SD compared to -0.85 SD, p < .0001). Small-for-gestational-age neonates were four times more likely to experience an increase in their weight z-score across their admission compared to neonates who were not small-for-gestational age (OR 4.04, 95% CI 2.23-7.48, p < .0001). Small-for-gestational-age neonates had an increased median length of stay, increased incidence of necrotizing enterocolitis but a reduced incidence of intraventricular hemorrhage. CONCLUSIONS: Preterm SGA babies experience a smaller reduction in their weight trajectory compared to their appropriately grown counterparts in the neonatal intensive care unit or special care nursery.

Detection of fetal arrhythmias in non-invasive fetal ECG recordings using data-driven entropy profiling.

Objective.Fetal arrhythmias are a life-threatening disorder occurring in up to 2% of pregnancies. If identified, many fetal arrhythmias can be effectively treated using anti-arrhythmic therapies. In this paper, we present a novel method of detecting fetal arrhythmias in short length non-invasive fetal electrocardiography (NI-FECG) recordings.Approach.Our method consists of extracting a fetal heart rate time series from each NI-FECG recording and computing an entropy profile using a data-driven range of the entropy tolerance parameterr. To validate our approach, we apply our entropy profiling method to a large clinical data set of 318 NI-FECG recordings.Main Results.We demonstrate that our method (TotalSampEn) provides strong performance for classifying arrhythmic fetuses (AUC of 0.83) and outperforms entropy measures such asSampEn(AUC of 0.68) andFuzzyEn(AUC of 0.72). We also find that NI-FECG recordings incorrectly classified using the investigated entropy measures have significantly lower signal quality, and that excluding recordings of low signal quality (13.5% of recordings) increases the classification performance ofTotalSampEn(AUC of 0.90).Significance.The superior performance of our approach enables automated detection of fetal arrhythmias and warrants further investigation in a prospective clinical trial.

Circulating SPINT1 Is Reduced in a Preeclamptic Cohort with Co-Existing Fetal Growth Restriction.

Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile). SPINT1 is also reduced in FGR diagnosed before 34 weeks' gestation. We hypothesised that circulating SPINT1 would be decreased in co-existing preterm preeclampsia and FGR. Plasma SPINT1 was measured in samples obtained from two double-blind, randomised therapeutic trials. In the Preeclampsia Intervention with Esomeprazole trial, circulating SPINT1 was decreased in women with preeclampsia who delivered SGA infants (n = 75, median = 18,857 pg/mL, IQR 10,782-29,890 pg/mL, p < 0.0001), relative to those delivering AGA (n = 22, median = 40,168 pg/mL, IQR 22,342-75,172 pg/mL). This was confirmed in the Preeclampsia Intervention 2 with metformin trial where levels of SPINT1 in maternal circulation were reduced in SGA pregnancies (n = 95, median = 57,764 pg/mL, IQR 42,212-91,356 pg/mL, p < 0.0001) compared to AGA controls (n = 40, median = 107,062 pg/mL, IQR 70,183-176,532 pg/mL). Placental Growth Factor (PlGF) and sFlt-1 were also measured. PlGF was significantly reduced in the SGA pregnancies, while ratios of sFlt-1/SPINT1 and sFlt1/PlGF were significantly increased. This is the first study to demonstrate significantly reduced SPINT1 in co-existing FGR and preeclamptic pregnancies.

PSG7 and 9 (Pregnancy-Specific ß-1 Glycoproteins 7 and 9): Novel Biomarkers for Preeclampsia.

Background Preeclampsia is pregnancy specific, involving significant maternal endothelial dysfunction. Predictive biomarkers are lacking. We evaluated the biomarker potential, expression, and function of PSG7 (pregnancy-specific ß-1 glycoprotein 7) and PSG9 (pregnancy-specific ß-1 glycoprotein 9) in preeclampsia. Methods and Results At 36 weeks gestation preceding term preeclampsia diagnosis, PSG7 and PSG9 (in Australian cohorts of n=918 and n=979, respectively) were significantly increased before the onset of term preeclampsia (PSG7, P=0.013; PSG9, P=0.0011). In samples collected at 28 to 32 weeks from those with preexisting cardiovascular disease and at high risk of preeclampsia (Manchester Antenatal Vascular Service, UK cohort, n=235), both PSG7 and PSG9 were also significantly increased preceding preeclampsia onset (PSG7, P<0.0001; PSG9, P=0.0003) relative to controls. These changes were validated in the plasma and placentas of patients with established preeclampsia who delivered at <34 weeks gestation (PSG7, P=0.0008; PSG9, P<0.0001). To examine whether PSG7 and PSG9 are associated with increasing disease severity, we measured them in a cohort from South Africa stratified for this outcome, the PROVE (Preeclampsia Obstetric Adverse Events) cohort (n=72). PSG7 (P=0.0027) and PSG9 (P=0.0028) were elevated among patients who were preeclamptic with severe features (PROVE cohort), but not significantly changed in those without severe features or with eclampsia. In syncytialized first trimester cytotrophoblast stem cells, exposure to TNFα (tumor necrosis factor α) or IL-6 (interleukin 6) significantly increased the expression and secretion of PSG7 and PSG9. In contrast, when we treated primary endothelial cells with recombinant PSG7 and PSG9, we only observed modest changes in Flt-1 (FMS-like tyrosine kinase-1) expression and Plgf (placental growth factor) expression, and no other effects on proangiogenic/antiangiogenic or endothelial dysfunction markers were observed. Conclusions Circulating PSG7 and PSG9 are increased before preeclampsia onset and among those with established disease with their production and release potentially driven by placental inflammation.

Circulating Activin A is elevated at 36 weeks' gestation preceding a diagnosis of preeclampsia.

Activin A is aberrantly expressed by the preeclamptic placenta and circulating levels have been investigated as a potential biomarker for the disease. In a nested case-control study we measured Activin A levels in maternal plasma at 28- and 36-weeks' gestation preceding term preeclampsia diagnosis. At 28 weeks Activin A was not significantly altered (n = 73 destined to develop preeclampsia vs n = 191 controls). At 36 weeks' gestation Activin A was significantly increased in 40 women destined to develop preeclampsia relative to 201 controls (p < 0.0001). These findings provide further validation of Activin A as a potential biomarker for subsequent term preeclampsia.

The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health.

Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.

A disintegrin and metalloproteinase 12 (ADAM12) is reduced at 36 weeks' gestation in pregnancies destined to deliver small for gestational age infants.

First trimester circulating ADAM12 is reduced in fetal growth restriction (FGR) and preeclampsia. We measured plasma ADAM12 at 36 weeks' gestation preceding diagnosis of term preeclampsia or delivery of a small for gestational age (SGA; birthweight <10th centile) infant in two independent cohorts (Cohort 1 90 SGA, 41 preeclampsia, 862 controls; Cohort 2121 SGA 23 preeclampsia; 190 controls). ADAM12 was reduced with SGA in both cohorts (p = 0.0015 and 0.011 respectively), and further reduced with birthweight <5th centile (p = 0.0013 and 0.0058 respectively). This validates ADAM12 as an SGA biomarker near term. Circulating ADAM12 preceding preeclampsia was not consistently altered.

Evaluation of Mesh and Sensor Resolution for Finite Element Modeling of Non-Invasive Fetal ECG Signals.

Non-invasive fetal electrocardiography (NI-FECG) is an emerging tool with novel diagnostic potential for monitoring fetal wellbeing using electrical signals acquired from the maternal abdomen. However, variations in the geometric structure and conductivity of maternal-fetal tissues have been shown to affect the reliability of NI-FECG signals. Previous studies have utilized detailed finite element models to simulate these impacts, however this approach is computationally expensive. In this study, we investigate a range of mesh and sensor resolutions to determine an optimal trade-off between computational cost and modeling accuracy for simulating NI-FECG signals. Our results demonstrate that an optimal refinement of mesh resolution provides comparable accuracy to a detailed reference solution while requiring approximately 12 times less computation time and one-third of the memory usage. Furthermore, positioning simulated sensors at a 20 mm grid spacing provides a sufficient representation of abdominal surface potentials. These findings represent default parameters to be used in future simulations of NI-FECG signals. Code for the model utilized in this work is available under an open-source GPL license as part of the fecgsyn toolbox.Clinical Relevance- Simulating NI-FECG signals provides the opportunity to study the effects of sensor placement and maternal-fetal anatomic variations in a controlled setting. This work has relevance in determining default parameters for efficiently performing these simulations.

Nicotinamide and its effects on endothelial dysfunction and secretion of antiangiogenic factors by primary human placental cells and tissues.

Preeclampsia is a serious pregnancy complication associated with elevated antiangiogenic markers and endothelial dysfunction. Recently nicotinamide (vitamin B3) was shown to reduce high blood pressure and proteinuria in mice models of the disease. Using primary human pregnancy tissue we show nicotinamide did not change antiangiogenic factor secretion including soluble fms-like tyrosine kinase 1 or soluble endoglin from primary cytotrophoblasts and placental explants. Furthermore, it did not reverse markers of endothelial dysfunction. Therefore, we did not demonstrate an effect of nicotinamide on reducing markers of preeclampsia from primary human placental tissues and vascular cells.

Circulating Tissue Factor Pathway Inhibitor (TFPI) is increased preceding preeclampsia diagnosis and in established preeclampsia.

INTRODUCTION: Tissue Factor Pathway Inhibitor (TFPI) is a part of the extrinsic coagulation pathway, and highly expressed in the placenta. We aimed to assess its potential as a preeclampsia biomarker. METHODS: Maternal plasma was prospectively collected at 36 weeks' gestation. Circulating TFPI was measured in a nested case-control group (39 women who developed preeclampsia, 98 controls), before being measured in a larger independent cohort along with Placental Growth Factor (PlGF; 41 who developed preeclampsia, 954 controls). Circulating TFPI was then measured in women with underlying vascular disease, and also assessed in the plasma and placentas from women with preterm preeclampsia (delivered at <34 weeks). RESULTS: Circulating TFPI was significantly increased in women destined to develop preeclampsia in the case-control study, a finding that validated in Cohort 2, with median TFPI in the preeclampsia group being 42.3 ng/ml (IQR 30-51 ng/ml) compared to 30 ng/ml (IQR 23.1-38.6 ng/ml) in controls (p < 0.0001). The area under the receiver operator characteristic curve (AUC) was 0.70. PlGF was significantly reduced in the preeclampsia group, and a ratio of TFPI/PlGF had an improved AUC of 0.78. In women with underlying vascular disease who were later diagnosed with early onset preeclampsia, circulating TFPI was significantly increased with a 0.29 (95% CI 0.13-0.44) increase in logTFPI (adjusted for gestation and hypertensive status). Circulating and placental TFPI were significantly increased in women with preterm preeclampsia. DISCUSSION: Circulating TFPI is increased in women preceding diagnosis of preeclampsia (at 36 weeks) and in women with preterm disease. TFPI may beneficially contribute to a multi-marker blood test to predict preeclampsia.

Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker.

Background We investigated the biomarker potential of growth differentiation factor 15 (GDF-15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF-15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia (P<0.001), area under the receiver operating characteristic curves (AUC) of 0.66 and 0.71, respectively. In cohort 2 a ratio of sFlt-1/PlGF (a clinical biomarker for preeclampsia) had a sensitivity of 61.0% at 83.2% specificity to predict those who will develop preeclampsia (AUC of 0.79). A ratio of GDF-15×sFlt-1/PlGF yielded a sensitivity of 68.3% at 83.2% specificity (AUC of 0.82). GDF-15 was consistently elevated across a number of international cohorts: levels were higher in placenta and blood from women delivering <34 weeks' gestation due to preterm preeclampsia in Melbourne, Australia; and in the blood at 26 to 32 weeks' gestation among 57 women attending the Manchester Antenatal Vascular Service (MAViS, UK) who developed preeclampsia (P=0.0002), compared with 176 controls. In the Preeclampsia Obstetric adVerse Events biobank (PROVE, South Africa), plasma GDF-15 was significantly increased in women with preeclampsia with severe features (P=0.02; n=14) compared to controls (n=14). Conclusions We conclude circulating GDF-15 is elevated among women more likely to develop preeclampsia or diagnosed with the condition. It may have value as a clinical biomarker, including the potential to improve the sensitivity of sFlt-1/PlGF ratio.

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria.

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.