There is little evidence evaluating angiogenic growth factor testing in real-world obstetric settings. This investigation evaluated maternal and perinatal pregnancy outcomes associated with maternal PlGF (placental growth factor) levels in real-world clinical care of high-risk pregnancies. From March 2017 to December 2019, 979 pregnant women with suspected risk of placental dysfunction, hypertensive disorders of pregnancy, or fetal growth restriction completed PlGF testing between 20+0 and 35+6 weeks of gestation. Maternal, fetal, and delivery characteristics were extracted through the electronic medical record system. The primary outcome of preterm birth was assessed using Royston-Parmar survival models and summarized with Kaplan-Meier methods. Of the 979 pregnant women, 289 had low PlGF levels (29.5%), and 690 had normal PlGF levels (70.5%). The survival probability of ongoing pregnancy free from preterm birth within 2- and 4-weeks following PlGF testing was significantly reduced in women with low PlGF levels, relative to women with normal PlGF levels (0.57 versus 0.99, standardized survival difference, −0.43 [95% CI, −0.76 to −0.09], and 0.37 versus 0.99, standardized survival difference, −0.62 [95% CI −0.87 to −0.38], respectively). Women with low PlGF levels were more likely to develop early-onset preeclampsia (adjusted odds ratio, 58.2 [95% CI, 32.1–105.4]) and have a stillbirth (adjusted odds ratio, 15.9 [95% CI, 7.6–33.3]). PlGF status distinguished placental from fetal causes of stillbirth. Low PlGF levels in high-risk pregnant women are strongly associated with increased rates of imminent preterm birth, as well as related adverse outcomes, including early-onset preeclampsia and stillbirth.

BackgroundHypertensive disorders complicating pregnancy are a major cause of maternal death. Our objective was to evaluate maternal clinical, hemodynamic, and placental prognostic indicators in a consolidated manner to identify women who develop hypertension in pregnancy.Methods and ResultsTwenty‐six normotensive pregnant women from a specialized Placenta Clinic at increased risk of developing de novo hypertension and 20 normotensive healthy pregnant controls were recruited at 22 to 26 weeks' gestation. Fourteen maternal clinical, hemodynamic, and placental characteristics were assessed in the second trimester and aggregated. Principal component analysis of this combined data set determined that 3 dimensions accounted for 56% of the cohort variability. The first dimension accounted for 31% of the cohort variability, with significant contributions from total peripheral resistance, endoglin, and cardiac output. The second dimension was predominantly influenced by body mass index and mean arterial pressure, while uric acid and myeloperoxidase mainly contributed to the third dimension. Unsupervised clustering identified 3 groups within this combined data set. Total peripheral resistance was the most significant distinguishing parameter between these groups (P<0.0001), followed by placental growth factor, endoglin, and cardiac output (P<0.0001). Using these 4 parameters, a receiver operating curve was constructed with an area under the curve of 0.975 (95% confidence interval 0.93–1) for the prediction of developing hypertension in pregnancy.ConclusionsConsolidated assessment of prognostic indicators in the second trimester of pregnancy may be useful to characterize and distinguish pathways by which women may develop hypertension in pregnancy. This approach could contribute to the development of pathway‐specific preventative and antihypertensive treatment strategies.

Preeclampsia is a hypertensive disorder of pregnancy characterized by new-onset hypertension with evidence of organ injury, affecting 2% to 8% of all pregnancies worldwide. 1 The majority of women with preeclampsia present clinically near term with favorable maternal and infant outcomes; however, a subset of women develop severe disease characterized by the need for preterm delivery typically before 34 weeks of gestation because of end-organ injury, severe hypertension, or intrauterine growth restriction.2 Women with severe preeclampsia demonstrate significant cardiovascular impairment during pregnancy and the immediate postpartum period and a higher risk of cardiovascular disease later in life.3-7 Given the significant shortand long-term maternal cardiovascular effects of preeclampsia, elucidating its pathogenesis has been of much interest in recent years. However, as yet, there is no agreement concerning the most effective pharmacological therapy for the prevention of preeclampsia in screen-positive women beyond aspirin, with clinical symptoms typically only resolving on delivery. Low molecular weight heparin (LMWH) has been evaluated for the prevention of various placenta-mediated pregnancy complications, including severe preeclampsia and recurrent miscarriage. Multiple trials and systematic reviews have concluded that LMWH reduces the incidence of recurrent severe preeclampsia in high-risk women, as well as perinatal mortality, preterm birth, and infant birth weight <10th percentile for gestational age, whereas other studies have found no treatment effect.9,10 Because the majority of previous trials have consisted of clinical end points, the mechanism of action of LMWH for the possible prevention of severe preeclampsia is currently unknown. Evidence suggests that observed beneficial effects do not result from heparin's anticoagulant actions within the placenta.11,12 An alternative hypothesis is that LMWH exerts vascular actions in the maternal compartment that reverse the systemic vascular dysfunction characteristic of preeclampsia. Previous trials in patients with coronary artery disease have determined that LMWH demonstrates beneficial endothelial effects, possibly through increased bioavailability of NO. 13,14The objective of the current study was to investigate the endothelial effects of LMWH in pregnant women at high risk of preeclampsia. We first compared baseline cardiovascular Abstract-Low molecular weight heparin (LMWH) has been investigated for the prevention of severe preeclampsia, although the mechanisms of action are unknown. The objective of this study was to investigate the cardiovascular effects of LMWH in pregnant women at high risk of preeclampsia. Pregnant women at high risk of preeclampsia (n=25) and low-risk pregnant controls (n=20) at 22 to 26 weeks' gestation underwent baseline cardiovascular assessments. Highrisk women were then randomized to LMWH or saline placebo (30 mg IV bolus and 1 mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post randomization. T...

BackgroundIt is well established that acute ischemic preconditioning (IPC) protects against ischemia–reperfusion (IR) injury; however, the effectiveness of repeated IPC exposure has not been extensively investigated. We aimed to determine whether daily IPC episodes provide continued protection from IR injury in a human forearm model, and the role of cyclooxygenase‐2 in these responses.Methods and ResultsThirty healthy volunteers were randomized to participate in 2 of 3 protocols (IR alone, 1‐day IPC, 7‐day IPC) in an operator‐blinded, crossover design. Subjects in the IR alone protocol underwent flow‐mediated dilation (FMD) measurements pre‐ and post‐IR (15′ upper‐arm ischemia and 15′ reperfusion). The 1‐day IPC protocol involved FMD measurements before and after 1 episode of IPC (3 cycles of 5′ upper‐arm ischemia and 5′ reperfusion) and IR. Day 7 of the 7‐day IPC protocol was identical to the 1‐day IPC protocol but was preceded by single daily episodes of IPC for 6 days prior. During each protocol, subjects received a 7‐day treatment of either the cyclooxygenase‐2 inhibitor celecoxib or placebo. Pre‐IR FMD was similar between groups. IR alone reduced FMD post‐IR (placebo, ΔFMD: −4.4±0.7%; celecoxib, ΔFMD: −5.0±0.5%). One‐day IPC completely prevented this effect (placebo, ΔFMD: −1.1±0.6%; celecoxib, ΔFMD: 0.0±0.7%; P<0.0001). Similarly, 7‐day IPC demonstrated persistent endothelial protection post‐IR (placebo, ΔFMD: −0.9±0.9%; celecoxib, ΔFMD: 0.0±0.8%; P<0.0001, P<0.0001 for ANOVA effect of IPC protocol). Celecoxib did not alter responses to IR in any protocol.ConclusionsDaily episodes of IPC provide sustained protection from IR‐induced endothelial dysfunction in humans through a mechanism that appears cyclooxygenase‐2‐independent.

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Low molecular weight heparin has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting. This review discusses the potential mechanisms of action of low molecular weight heparin for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization. Preeclampsia preventionPreeclampsia is a hypertensive disorder of pregnancy, clinically diagnosed by new-onset hypertension after 20 weeks' gestation with evidence of organ injury [1]. The potential maternal and perinatal complications of preeclampsia are significant, including maternal seizures, fetal growth restriction (FGR) and stillbirth. Approximately 5% of women develop preeclampsia, with the majority of women experiencing mild preeclampsia that occurs near term and is safely managed by delivery [2]. Only 1% of pregnant women develop early-onset preeclampsia, where both the maternal and fetal implications are substantially greater, typically resulting in FGR and the need for iatrogenic preterm delivery before 34 weeks' gestation [2]. Early-onset preeclampsia is hypothesized to be a direct consequence of the interactions between a dysfunctional placenta and maternal cardiovascular system, while late-onset preeclampsia is hypothesized to be largely triggered by maternal constitutional factors [3][4][5]. Typically, women with early-onset preeclampsia present with an acute, severe syndrome that threatens the life of both the mother and her fetus. In contrast, late-onset preeclampsia is a less severe illness with a favourable clinical outcome in countries with well-developed maternity systems. However, in countries with limited medical resources, preeclampsia remains among the most frequent causes of maternal death [6].The early-and late-onset subsets of preeclampsia exhibit different types and severity of placental pathologies and express divergent maternal haemodynamics. Early-onset preeclampsia is strongly associated with placental disease characterized by maternal vascular malperfusion, where the abnormal placental villi secrete excessive amounts of antiangiogenic proteins and reduced levels of pro-angiogenic proteins into the maternal circulation [7][8][9]. Women with early-onset disease, typically associated with FGR, develop hypertension earlier in pregnancy that is characterized by increased systemic vascular resistance, reduced cardiac output and stroke volume along with relative bradycardia [5]. In contrast, late-onset preeclampsia is less commonly associated with severe placental disease, and consequently exhibits less British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 673-678 673

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Sildenafil and nitroglycerin (GTN) are effective pharmacological preconditioning agents, protecting from the adverse effects of ischemia and reperfusion (I/R). The objective of the present study was to determine whether repeated, daily administration of sildenafil or GTN provides sustained preconditioning from I/R in the human forearm vasculature. Thirty-six healthy volunteers participated in this investigator-blind, randomized, placebo-controlled trial. Subjects received transdermal GTN (0.6 mg/h, 2 h/day), sildenafil (50 mg once daily), or placebo. Twenty-four hours after the first dose of medication, subjects underwent an assessment of flow-mediated dilation (FMD) before and after I/R (15 min of upper arm ischemia followed by 15 min of reperfusion). Subjects continued their study medication for 7 days, at which point FMD measurements were repeated before and after I/R. Venous blood samples were obtained for the determination of myeloperoxidase, P-selectin, and myoglobin before and after each I/R episode. Twenty-four hours after the first dose, both sildenafil and GTN (but not placebo) provided protection from the adverse effects of I/R. After 7 days of repeated daily doses and 24 h after the last dose, FMD was significantly blunted after I/R in placebo- and GTN-treated groups. In contrast, repeated daily administration of sildenafil provided continued protection from the adverse effects of I/R on endothelial function. There was no significant change in plasma levels of myeloperoxidase, P-selectin, or myoglobin at any time point. In conclusion, the present study establishes, for the first time in humans, that sildenafil, but not GTN, provides sustained pharmacological preconditioning of the endothelium and protection from adverse I/R effects on vascular function.