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Preeclampsia (PE) is a pregnancy disease characterized by maternal hypertension and vascular dysfunction. PE is believed to originate from the ischemic/hypoxic placenta that activate local HIF-1α-mediated release of anti-angiogenic sFlt-1 and release of inflammatory cytokines, such as TNF-α. Signaling from both sFlt-1 and TNF-α-induced NF-κB activation result in upregulation of the potent vasoconstrictor ET-1. Antagonism of ET-1 signaling has been shown to relieve symptoms in animal models of PE, but these treatments are contraindicated in pregnancy. Luteolin is a naturally occurring bioflavonoid that has been studied for its use as an anti-inflammatory and anti-hypertensive agent but has never been studied in PE. In this in vitro study, we tested the hypothesis that luteolin may attenuate pathways involved in vascular dysfunction by attenuating HIF-1α increase (via upstream PI3K and ERK) as well as TNF-α-induced NF-κB activation. To study HIF-1α inhibition by luteolin, placental explants from normotensive patients were treated under normoxic (20%) and hypoxic (2%) conditions with luteolin (10μM) for 72 hours, in the presence and absence of relevant inhibitors; PI3K inhibitor (LY294002, 50μM) and ERK inhibitor (U0126, 20μM). Western blots were used to measure HIF-1α protein changes. HUVEC cells were stimulated by TNF-α in the presence or absence of luteolin to determine NF-κB nuclearization by immunofluorescence.Hypoxic incubations significantly increased HIF-1α compared to normoxia (1.44 + 0.43 vs 0.55 + 0.21 arbitrary units (AU); p This work was supported by NIH 1R56HL157579-01. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.

Preeclampsia is associated with significant morbidity and mortality for mother and baby. Although around 30% of all pregnancies are evaluated for preeclampsia, diagnosis is difficult, especially in patients who have overlying symptoms from other diseases. Discovery of circulating angiogenic factors in the pathogenesis of preeclampsia has been a major advance for both diagnosis and prognosis. The anti-angiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1) and the pro-angiogenic factor, placental growth factor (PlGF), can be measured in plasma and serum and are usually reported as a ratio, which specifically relates to the onset and severity of preeclampsia. The sFlt-1/PlGF ratio has a very high negative predictive value in ruling out the development of preeclampsia within 7 days among women with suspected preeclampsia. Currently, there is no clear consensus on the practical use of angiogenic biomarkers in the detection and management of preeclampsia in routine clinical practice. While major international clinical guidelines exist, they do not define which specific parameters signal patient admission, or outpatient evaluation of suspected preeclampsia, and most clinicians follow local practices. Better guidance is needed on risk stratification among women with suspected preeclampsia, as well as among women at high risk for preeclampsia. Prediction of adverse outcomes in women, after the clinical diagnosis of preeclampsia, is also important. This report has been developed following a meeting of international experts and aims to guide clinicians in the management of pregnant women at risk of preeclampsia using the sFlt-1/PlGF ratio test.

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Background Preeclampsia is a leading cause of maternal and neonatal mortality and morbidity worldwide. Diagnosis of the condition is currently limited to utilization of nonspecific signs and symptoms. However, identification of potential pathogenic biomarkers may support earlier diagnosis and ultimately improved prognosis. Content The current models of preeclampsia suggest that the disease has components of abnormal placentation, a degree of angiogenic imbalance and endothelial dysfunction. Angiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin increase while placental growth factor concentrations decrease in the circulation weeks before the onset of the disease. Multiple studies have looked at the capacity of angiogenic factors for the prediction of preeclampsia and adverse pregnancy outcomes. Summary The goal of this review is to focus on the role of angiogenic factors in the pathogenesis of preeclampsia and use of angiogenic biomarkers for risk stratification, diagnosis, and prognosis of the disease.

Hypertensive disorders of pregnancy (HDP) remain one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Affected women are also at increased risk for cardiovascular disease later in life, independently of traditional cardiovascular disease risks. Despite the immediate and long-term cardiovascular disease risks, recommendations for diagnosis and treatment of HDP in the United States have changed little, if at all, over past decades, unlike hypertension guidelines for the general population. The reasons for this approach include the question of benefit from normalization of blood pressure treatment for pregnant women, coupled with theoretical concerns for fetal well-being from a reduction in utero-placental perfusion and in utero exposure to antihypertensive medication. This report is based on a review of current literature and includes normal physiological changes in pregnancy that may affect clinical presentation of HDP; HDP epidemiology and the immediate and long-term sequelae of HDP; the pathophysiology of preeclampsia, an HDP commonly associated with proteinuria and increasingly recognized as a heterogeneous disease with different clinical phenotypes and likely distinct pathological mechanisms; a critical overview of current national and international HDP guidelines; emerging evidence that reducing blood pressure treatment goals in pregnancy may reduce maternal severe hypertension without increasing the risk of pregnancy loss, high-level neonatal care, or overall maternal complications; and the increasingly recognized morbidity associated with postpartum hypertension/preeclampsia. Finally, we discuss the future of research in the field and the pressing need to study socioeconomic and biological factors that may contribute to racial and ethnic maternal health care disparities.

Patients with a history of hypertensive disorders of pregnancy (HDP) suffer higher rates of long-term cardiovascular events including heart failure, coronary artery disease, and stroke. Cardiovascular changes during pregnancy can act as a natural stress test, subsequently unmasking latent cardiovascular disease in the form of HDP. Because HDP now affect 10% of pregnancies in the United States, the American Heart Association has called for physicians who provide peripartum care to promote early identification and cardiovascular risk reduction. In this review, we discuss the epidemiology, pathophysiology, and outcomes of HDP-associated cardiovascular disease. In addition, we propose a multi-pronged approach to support cardiovascular risk reduction for women with a history of HDP. Additional research is warranted to define appropriate blood pressure targets in the postpartum period, optimize the use of pregnancy history in risk stratification tools, and clarify the effectiveness of preventive interventions. The highest rates of HDP are in populations with poor access to resources and quality health care, making it a major risk for inequity of care. Interventions to decrease long-term cardiovascular disease risk in women following HDP must also target disparity reduction.

Maternal mortality is a worldwide epidemic, with rates in the United States far surpassing those in similar high-income countries, and years of implicit bias and systemic racism have impacted outcomes for individuals belonging to racial and ethnic minorities. Structural racism must be dismantled to ensure better care for all.

Background The flavonoid, luteolin, promotes vasorelaxation in various arteries through endothelial-dependent and independent mechanisms. Although there is growing interest in the vasoactive effects of flavonoids on maternal vascular function during pregnancy, it is unknown whether luteolin elicits vasorelaxation in the uterine circulation. We tested the hypothesis that luteolin induces vasorelaxation via endothelial-dependent mechanisms in uterine arteries from normal pregnant rats during late gestation. Methods Uterine arteries and aortas were isolated from Sprague-Dawley rats at gestational day 19 and prepared for wire myography. Results The potency of luteolin-induced vasorelaxation was examined between uterine arteries and the aortas. By 50 µM of luteolin, there was complete relaxation (100.5 ± 5.2%) in uterine arteries as compared to aortas (27.5 ± 10.0%). Even the highest concentration of 100 µM luteolin produced less than half relaxation (43.6 ± 8.6%) in aortas compared to uterine arteries. We then explored if luteolin-induced vasorelaxation in uterine arteries from pregnant rats was mediated by endothelial-dependent vasorelaxation pathways, including nitric oxide synthase (NOS), cyclooxygenase (COX), or potassium (K+) channels. Blocking these pathways with N(G)-Nitro- l -arginine methyl ester hydrochloride (L-NAME), indomethacin, or tetraethylammonium (TEA)/high potassium chloride (KCl), respectively, did not alter luteolin responses in uterine arteries from pregnant rats. These findings suggested that endothelial factors may not mediate luteolin-induced vasorelaxation in uterine arteries during pregnancy. Indeed, experiments where the endothelium was removed did not alter luteolin-induced vasorelaxation in uterine arteries during pregnancy. Conclusions Luteolin directly promotes vasorelaxation in the medial smooth muscle layer of uterine arteries during normal pregnancy.

Supplemental Digital Content is available in the text., This study evaluated whether planned early delivery would ameliorate cardiovascular dysfunction 6 months postpartum, compared with usual care with expectant management, in women with late preterm preeclampsia. We conducted a mechanistic observational study in women with preterm preeclampsia between 34+0 and 36+6 weeks’ gestation, nested within a randomized controlled trial of planned early delivery versus expectant management (usual care), in 28 maternity hospitals in England and Wales. Women were followed up 6 months postpartum with cardiovascular assessments. The primary outcome was a composite of systolic and diastolic dysfunction (by 2009 and 2016 definitions of diastolic dysfunction). Between April 27, 2016, and November 30, 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited. One hundred thirty-three women were randomized to planned delivery, 137 women were randomized to expectant management within the trial, while 150 women received expectant management outside of the trial. 321 (76.4%) completed their 6 month echocardiography assessment. 10% (31/321) had a left ventricular ejection fraction

Introduction: Peripartum cardiomyopathy (PPCM) is a rare form of pregnancy-related heart failure associated with preeclampsia. Our understanding of their shared pathophysiology is limited as are treatment options. Hypothesis: We hypothesized that plasma proteomic profiling would identify deleterious circulating proteins and provide insights into shared mechanisms driving preeclampsia and PPCM. Methods: We performed serum proteomic case-control studies in women with preeclampsia or PPCM to identify biological processes common to both conditions. The top candidate was validated in independent preeclampsia (n=58) and PPCM (n=114) cohorts. Preeclamptic placenta was examined as a potential source of circulating proteins. Therapeutic targeting the top candidate was examined in an animal model of PPCM. Results: Paradoxically, we found the senescence-associated secretory phenotype (SASP), a marker of biological aging, to be the most upregulated process in relatively young women with preeclampsia (normalized enrichment score [NES]=3.3;p adj =4.0x10 -6 ) or PPCM (NES=3.2;p adj =1.9x10 -5 ). 28 circulating proteins contributed to this common signal, and were strongly enriched in preeclamptic placenta, which expressed markers of increased senescence. The TGFb family member, Activin-A, was the most highly upregulated SASP gene in preeclamptic placentas (5-fold;p Conclusions: These data implicate placental senescence in the increased deleterious circulating proteins seen in preeclampsia and PPCM. We identify multiple new circulating factors associated with these diseases and demonstrate that targeting SASP proteins, such as Activin-A, can mitigate PPCM in mice.

Objective Preeclampsia is a major obstetric disorder that can lead to severe maternal, fetal and infant outcomes. In women with suspected preeclampsia, measurement of the soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) ratio has been shown to have a high negative predictive value (>97%). Our aim was to estimate the value to the US healthcare system of adopting this test into clinical practice. Study design: An economic model was developed for the evaluation of suspected preeclampsia from a US payer perspective using data from a US observational study of 459 women evaluated between 23 and 34.6 weeks. Test results were not available to clinicians. The model compares two strategies for managing suspected preeclampsia: standard care versus a biomarker-informed pathway utilizing the sFlt1/PlGF ratio. Results Utilization of the sFlt1/PlGF ratio test reduced the number of women admitted for suspected preeclampsia by 34–49%. Despite fewer admissions, a higher proportion of women admitted to hospital subsequently developed preeclampsia, and the proportion of women not admitted who would subsequently develop preeclampsia remained low (3.2%–6.7%). Cost savings arising from a reduction in admissions are estimated to be $1050 in the base case; varying the hospitalization cost ±25% would lead to savings in the range $771 to $1330 per patient at 2020 prices. Conclusion Adopting the sFlt1/PlGF ratio test as an adjunct to clinical criteria improves the assessment of risk in women presenting with suspicion of preeclampsia and has the potential to safely reduce unnecessary admissions and save costs.

Objective To study the association between hypertensive diseases of pregnancy and immediate postpartum development of heart failure in a large national database. Patients and Methods Using the 2013 to 2014 National Readmissions Database, which covered admissions from January 1 through September 30 in years 2013 and 2014, we examined 90-day readmission rates in parturients with a diagnosis of hypertensive disease of pregnancy who were discharged after delivery. The primary outcome was the association between the presence of hypertensive disease of pregnancy and readmission with heart failure within 90 days of delivery discharge. Secondary outcomes included readmission mortality, time between delivery discharge and readmission, length of stay, and costs of readmission. Results Women with hypertensive disease of pregnancy were more likely to be readmitted with heart failure (1809 of 25,908 readmissions (7.0%) vs 2622 of 89,660 readmissions (2.9%); P Conclusion Parturients with hypertensive disease of pregnancy were more likely to be readmitted with heart failure within 90 days of delivery. Most patients readmitted with heart failure were readmitted within 2 weeks of discharge after delivery. Patients readmitted with heart failure had substantial health care expenditures.

Hypertensive disorders of pregnancy—chronic hypertension, gestational hypertension, and preeclampsia—are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women.

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [ P *]=1.2×10 –46 ). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P *=7.0×10 –8 ), DSP (odds ratio=14.9, P *=1.0×10 –8 ), and BAG3 (odds ratio=53.1, P *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P =2.5×10 –4 ), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

Persistent postpartum hypertension is a significant cause of maternal morbidity. Our objective was to study the effect of furosemide on postpartum blood pressure recovery in women with hypertensive disorders of pregnancy. We performed a randomized, double-blind, placebo controlled trial of a 5-day course of 20mg oral furosemide versus placebo in women with gestational hypertension and preeclampsia with/without severe features from June 2018 to October 2019. Primary outcomes were persistent hypertension at 7-days postpartum (using generalized linear models to calculate adjusted relative risk) and days to resolution of hypertension (Kaplan Meier curves), stratified by severe/non-severe hypertensive disease. Secondary outcomes included readmissions and need for additional hypertensive medication.We randomized 384 women (192/group). Baseline characteristics were similar except cesarean delivery rate was higher in the furosemide group (29% vs. 20%, p=0.04). In women randomized to furosemide, there was a 60% reduction in the prevalence of persistently elevated blood pressure at 7-days when controlling for cesarean (aRR 0.40, 95%CI 0.20–0.81). The magnitude of reduction was greater in women with non-severe disease (aRR 0.26, 95% CI 0.10–0.67). Days to blood pressure resolution was significantly shorter among women with non-severe disease randomized to furosemide (8.5 vs. 10.5, p=0.001). There were no significant differences in readmissions or need for additional antihypertensive medication postpartum between groups. In this double-blinded randomized trial, a short course of postpartum furosemide significantly improved blood pressure control in women with hypertensive disorders of pregnancy, mostly among women without severe disease.

Background Preeclampsia is a prominent risk factor for long‐term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (−18.3% versus −21.3%, P =0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P =0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P =0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P =0.02) and activin/follistatin‐like 3 ratio (0.03 versus 0.02, P =0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index ( P =0.003). Conclusions Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long‐term cardiac function.

Objectives Ischemic placental disease (IPD), including preeclampsia, abruption, and fetal growth restriction, often recurs in subsequent pregnancies. Angiogenic factors of placental origin have been implicated in the pathogenesis of preeclampsia, but have not been studied as predictors of IPD in subsequent pregnancies. We hypothesized that elevated angiogenic factors in an index pregnancy would be associated with recurrence of IPD. Study design We conducted a retrospective cohort study of patients undergoing evaluation for preeclampsia who had angiogenic factors measured in an index pregnancy and experienced a subsequent pregnancy at the same institution. Patients with IPD in the index pregnancy were included. A high ratio of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) was defined as greater than or equal to 85. Main outcome measures The primary outcome was IPD in a subsequent pregnancy. Results We included 109 patients in the analysis. The sFlt1/PlGF ratio was elevated in 30% of participants. Those with an elevated ratio were more likely to be nulliparous in the index pregnancy, and less likely to have chronic hypertension. The recurrence of IPD in the study was 27%, with a non-significant difference in risk based on a high sFlt-1/P1GF ratio RR 0.58 (95% CI 0.21 – 1.6) compared to a low ratio. Conclusions A high sFlt1/P1GF ratio in an index pregnancy is not associated with a higher risk of IPD in a subsequent pregnancy. These data suggest placental angiogenic biomarkers are specific to the pregnancy and not a reflection of maternal predisposition to IPD.

Background Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain ( GLS ), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin. To test our hypothesis, we performed a cohort study of women with preeclampsia or superimposed preeclampsia and compared activin A levels and GLS in parturients who did or did not receive aspirin. Methods and Results Ninety‐two parturients were enrolled, of whom 25 (27%) received aspirin (81 mg/day) therapy. GLS , plasma activin A, and follistatin, which inactivates activin A, were measured. Women receiving aspirin therapy had lower median (interquartile range) levels of activin A (8.17 [3.70, 10.36] versus 12.77 [8.37, 31.25] ng/mL; P =0.001) and lower activin/follistatin ratio (0.59 [0.31, 0.93] versus 1.01 [0.64, 2.60] P =0.002) than women who did not receive aspirin, which also remained significant after multivariable analysis. Furthermore, GLS was worse in patients who did not receive aspirin (−19.84±2.50 versus −17.77±2.60%; P =0.03) despite no differences in blood pressure between groups. Conclusions Our study suggests that antepartum aspirin therapy reduced serum activin A levels and improved GLS in preeclamptic patients, suggesting that aspirin may mitigate the postpartum cardiac dysfunction seen in women with preeclampsia.

Women with hypertensive disorders of pregnancy have an increased risk of subsequent heart failure and cardiovascular disease when compared with women with normotensive pregnancies. Although the mechanisms underlying these findings are unclear, elevated levels of the biomarker activin A are associated with myocardial dysfunction and may have predictive value. We hypothesized that elevated levels of antepartum activin A levels would correlate with postpartum cardiac dysfunction in women with hypertensive disorders of pregnancy. We prospectively studied 85 women to determine whether increased antepartum activin A levels were associated with cardiac dysfunction at 1 year postpartum as measured by global longitudinal strain. Thirty-two patients were diagnosed with preeclampsia, 28 were diagnosed with gestational or chronic hypertension, and the remainder were nonhypertensive controls. Activin A levels were measured with ELISA both in the third antepartum trimester and at 1 year postpartum. Comprehensive echocardiograms including measurement of global longitudinal strain were also performed at enrollment and at 1 year postpartum. Antepartum activin A levels correlated with worsening antepartum global longitudinal strain ( r =0.70; P =0.0001). Across the entire cohort, elevated antepartum activin A levels were associated with the development of abnormal global longitudinal strain at 1 year (C statistic 0.74; P =0.004). This association remained significant after multivariable adjustment for clinically relevant confounders (C statistic 0.93; P =0.01). Postpartum activin A levels also correlated with increasing left ventricular mass index ( P =0.02), increasing mean arterial pressures ( P =0.02), and decreasing E′ values ( P =0.01). Activin A may be a useful tool for identifying and monitoring patients at risk for postpartum development of cardiovascular disease.

Background Preeclampsia is a leading hypertensive disorder in pregnant women. The angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio, have been shown to be associated with diagnosis and prediction of preeclampsia. The objective of this study is to validate the analytical performance of sFlt-1 and PlGF on the Cobas e602 system (Roche Diagnostics Corporation). Method Intra-day and inter-day precisions for both sFlt-1 and PlGF assays were assessed using quality control materials provided from Roche Diagnostics. The accuracies for both assays were assessed by running 60 patient samples, which have been previously analyzed on the Elecsys 411 analyzer (Roche Diagnostics Corporation) at the Beth Israel Deaconess Medical Center. Linearity studies for both assays were performed using patient plasma spiked with recombinant sFlt-1 and PlGF proteins (R&D systems). Hemolysis, icterus, lipemia and biotin interference studies were performed by spiking hemolysate, bilirubin, intralipid or biotin into either pooled patient plasma with detectable levels of sFlt-1 and PlGF or otherwise, patient plasma spiked with recombinant sFlt-1 and PlGF proteins. Results Total precisions for both assays demonstrated CVs of 0.98). Lower limit of quantitation (10% CV) was 30 pg/mL for sFlt-1 and 7 pg/mL for PlGF, respectively. Interference studies showed sFlt-1 and PlGF were not significantly affected by hemolysis up to H-indices of 500 and 1000 respectively; both assays were not affected by bilirubin up to an I-index of 60, and lipemia up to an L-index of 2800. Biotin at concentrations >30 ng/mL caused significant negative bias for both sFlt-1 and PlGF assays. Comparison studies showed the following: Cobas e602 sFLT-1 = 1.09 [Elecsys 411 sFLT-1] +203 (r2=0.97, Sy/x=1234, n=58); Cobas e602 PlGF = 1.10 [Elecsys 411 PlGF] +47 (r2=0.99, Sy/x=22.1, n=58); Cobas e602 sFLT-1/PlGF ratio = 0.94 [Elecsys 411 sFLT-1/PlGF ratio] +3.5 (r2=0.91, Sy/x=50, n=58). Conclusion sFlt-1 and PlGF measured on Roche Diagnostics Cobas e602 system demonstrated excellent analytical performance and are acceptable for clinical use once approved in the US.

The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension, and proteinuria that resolve with placental delivery have been linked to an extracellular protein made by the placenta, soluble fms-like tyrosine kinase 1 (sFlt1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix bound, gain access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta's outermost layer, the syncytiotrophoblast, forms abundant “knots” that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50–150 μm diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in the third-trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder.

Preeclampsia-related morbidity and mortality is rising predominantly because of delayed identification of patients at risk for preeclampsia with severe features and associated complications. This study explored the association between angiogenic markers (sFlt1 [soluble fms-like tyrosine kinase-1]) and PlGF [placental growth factor]) and preeclampsia-related peripartum complications. Normotensive women or those with hypertensive disorders of pregnancy were enrolled. Blood samples were collected within 96 hours before delivery, and angiogenic markers were measured on an automated platform. Our study included 681 women, 375 of which had hypertensive disorders. Of these, 127 (33.9%) had severe preeclampsia, and 71.4% were black. Compared with normotensive women, women with severe preeclampsia had higher levels of sFlt1 (9372.5 versus 2857.0 pg/mL; P P P P P valuesP =0.004). This study demonstrates a significant association between an abnormal angiogenic profile before delivery and severe preeclampsia and peripartum complications.

Hypertensive disorders of pregnancy (HDP) are associated with subclinical changes in cardiac function. Although the mechanism underlying this finding is unknown, elevated levels of soluble antiangiogenic proteins such as soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng) are associated with myocardial dysfunction and may play a role. We hypothesized that these antiangiogenic proteins may contribute to the development of cardiac dysfunction in HDP. We prospectively studied 207 pregnant women with HDP and nonhypertensive controls and evaluated whether changes in global longitudinal strain (GLS) observed on echocardiography is specific for HDP and whether these changes correlate with HDP biomarkers, sFlt1 and sEng. A total of 62 (30%) patients were diagnosed with preeclampsia (group A), 105 (51%) did not have an HDP (group B), and 40 (19%) were diagnosed with chronic or gestational hypertension (group C). Blood was drawn and sFlt1 and sEng levels measured using enzyme-linked immunosorbent assay. Comprehensive echocardiograms, including measurement of GLS, were performed on all patients. Overall, GLS was worse in women in group A (preeclampsia) than those in group B or C. Increasing sFlt1 and sEng levels correlated with worsening GLS ( r =0.44 for sFlt1 and r =0.46 for sEng, both P r =0.18 and r =0.22, both P ≤0.01). Increasing levels also correlated with increasing left ventricular mass index, which also remained significant after multivariable analysis ( r =0.20 for sFlt1 and 0.19 for sEng, both P =0.01). Elevated circulating levels of antiangiogenic proteins in HDP correlate with and may contribute to myocardial dysfunction as measured by GLS.

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight P interaction =0.005), but more preterm birth ( P interaction =0.043), and no effect on perinatal death or high-level neonatal care >48 hours ( P interaction =0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks ( P interaction =0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes. Clinical Trial Registration— URL: https://www.isrctn.com . Unique identifier: ISRCTN71416914.

Background Household air pollution (HAP) is associated with adverse pregnancy outcomes. Objectives Investigate impact of in-utero HAP exposure on placental development and chronic hypoxia. Methods Markers of chronic placental hypoxia [Hofbauer cells (HBC), syncytial knots (SK), chorionic vascular density (cVD) and hypoxia-inducible factor (HIF)] were stained by hematoxylin-eosin and/or immunohistochemically in placenta samples collected from firewood −/kerosene-users (A, n = 16), and ethanol-users (B, n = 20) that participated in a randomized controlled intervention trial in Ibadan, Nigeria. A third group of non-smoking and presumed natural gas-using Chicago women (C, n = 12) were included in this exploratory pilot to assess for possible differences in placenta histology between similar racial groups. All patients had uncomplicated pregnancies and delivered at term. Results HBC, SK and cVD were significantly increased among firewood-/kerosene-users compared to ethanol-users and natural gas-using Chicago women (HBC medians 5.5, 3.5, and 2.0, respectively; SK means 55.6, 41.8 and 30.1; cVD means 8.8, 6.2, and 5.2; all p p Conclusions In-utero exposure to HAP is associated with pathologic changes and HIF expression consistent with chronic hypoxia in placenta of firewood/kerosene-users compared to ethanol-users with less HAP exposure and Chicago women with no presumed HAP exposure. Presence of chronic hypoxic signature in placenta of women exposed to HAP has implications for adverse pregnancy complications and future growth and development of the young children. Future larger studies need to focus on HAP exposure and placental disorders like preeclampsia and long-term health impact of in-utero exposure to HAP.

Background Maternal exposure to ambient air pollution affects placental growth markers. Objectives Investigate impact of household air pollution (HAP) on placental growth markers. Methods Two groups of pregnant women were identified: firewood/kerosene stove-users (A, n = 33) and bioethanol stove-users (B, n = 44) that participated in a randomized control trial in Ibadan, Nigeria. A third group of non-smoking and presumed liquefied petroleum gas-using Chicago women (C, n = 19) were included in this exploratory pilot to assess for possible differences between similar racial groups. Levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) were measured in maternal and cord plasma using ELISA. Results Maternal and cord blood sFlt-1 and PlGF did not differ significantly between women of groups A and B. Nevertheless, both groups differed significantly from the Chicago group in that group A women had lower maternal sFlt-1 (1372.50 vs. 3194.19) but higher PlGF (1607.87 vs. 442.80), and higher cord blood sFlt-1 (2925.02 vs. 107.53) and PlGF (223.68 vs. 6.92), all p ≤ 0.001. Group B showed similar trends (all p ≤ 0.002). Maternal PlGF levels were positively correlated to minutes of HAP exposure when PM 2.5 concentration was above 100 μg/m 3 in Nigerian women. Conclusions Maternal levels of PlGF and cord blood levels of sFlt-1 and PlGF in Nigerian women with varying HAP exposures were significantly higher than Chicago-based women who had no presumed HAP exposure. It suggests that in-utero exposure to HAP influenced levels of angiogenic factors involved in normal placentation and growth and could represent compensation for pollutants exposure to preserve fetal viability.

See related article, pp 469–474 Preeclampsia is a leading cause of morbidity and mortality in mothers particularly in the developing world.1 Sub-Saharan Africa and South Asia collectively account for 86% of global maternal deaths, and a substantial percentage of these deaths is attributed to preeclampsia and related disorders. Historically, preeclampsia had been primarily viewed as medically important because it could presage eclamptic seizures. The word eclampsia derived from the Greek word for lightening refers to the sudden and unpredictable convulsive phase of a form of hypertension specific to preeclampsia. However, in the past century, it became apparent that preeclampsia is a dangerous condition in its own right; not only preconvulsive but also presevere hypertension, pre–HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), prerenal failure, pre-abruption, prefetal death, and prenumerous complications related to the specific disorder, which also affects cardiac and renal health later in life. In developed countries, most women have adequate access to prenatal care and therefore are seen regularly for blood pressure and spot urine protein check. In this setting, if there is a concern for preeclampsia, the patient is usually admitted for frequent monitoring of blood pressures, laboratory work, management of hypertension, administration of betamethasone for fetal lung maturity, and close observation for development of warning signs that may indicate the need for delivery.2 Despite the absence of specific tests to predict complications, this management and treatment plan has resulted in a dramatic reduction of maternal deaths related to preeclampsia, though at the cost of increased rates of …

BACKGROUND Asian American/Pacific Islanders (AAPIs) are the fastest-growing racial group in the United States. Despite a higher socioeconomic status, AAPI women experience higher rates of maternal morbidity and mortality. METHODS Using the National Inpatient Sample, we performed a retrospective cohort analysis of women who were hospitalized for delivery from 2002 to 2013. The primary outcome variable was inpatient mortality rate, and the presence of severe maternal morbidities was estimated using the Bateman Comorbidity Index, a validated tool for predicting obstetric morbidity. RESULTS AAPI women presenting for delivery between 2003 and 2012 were older, more likely to reside in a zip code in the top quartile of annual income, be privately insured than Caucasian women, and less likely to have a higher Bateman Comorbidity Index. However, AAPI women had a higher likelihood of postpartum hemorrhage (3.4% vs 2.7%, P < .001), uterine atony, severe perineal lacerations, and severe maternal morbidities. Procedures such as transfusion, hysterectomy, and mechanical ventilation were also more common in AAPI women. Furthermore, AAPI women had a higher mortality rate that persisted despite adjustment for an apparently higher income and comorbidities (odds ratio 1.72, 95% confidence interval: 1.14-2.59, P = .01). CONCLUSIONS Despite having a higher socioeconomic status, AAPI women had higher rates of maternal mortality during hospitalization for delivery. This increase persisted even after adjustment for factors known to affect peripartum outcomes. Further investigation is needed to better clarify the causes of racial differences in maternal morbidity and mortality.

Objective: To study the association between cardiac function measured by myocardial performance index (MPI), blood pressures and angiogenic factors measured at the time of echocardiography in patients with and without hypertensive disorders of pregnancy (HDP). Methods: We prospectively studied 189 pregnant women and evaluated whether changes in cardiac function observed on echocardiography were correlated with higher blood pressures and whether higher blood pressures were associated with antiangiogenic proteins (soluble fms-like tyrosine kinase, sFlt1; soluble endoglin, sEng). Comprehensive echocardiograms, including measurement of MPI, were performed on all patients. sFlt1 and sEng levels were measured using enzyme-linked immunosorbent assay. Results: Overall, 189 patients were divided into tertiles based on mean arterial pressure (MAP). The MPI was worst in tertile 3 (0.50 ± 0.15) compared to tertile 1 (0.42 ± 0.10), p = 0.0004. sFlt1 (pg/ml) and sEng (ng/ml) were highest in tertile 3 compared to tertile 1: 15055.37 vs. 1623.01 and 33.06 vs. 8.15, respectively, with p-value Conclusion: Mean arterial pressure correlates with worsening cardiac function as measured by MPI and serum levels of angiogenic factors. Further studies are needed to evaluate whether a reduction in blood pressure will reverse changes in MPI or reduce levels of angiogenic proteins seen among women with HDP.

This study aimed to investigate the relationship between maternal hypertensive disease and other risk factors and the neonatal development of necrotizing enterocolitis (NEC).This was a retrospective case-control study of infants with NEC from 2008 to 2012. The primary exposure of interest was maternal hypertensive disease, which has been hypothesized to put infants at risk for NEC. Other variables collected included demographics, pregnancy complications, medications and neonatal hospital course. Data were abstracted from medical records.Twenty-eight cases of singleton neonates with NEC and 81 matched controls were identified and analyzed. There was no significant difference in the primary outcome. Fetuses with an antenatal diagnosis of growth restriction were more likely to develop NEC (p = 0.008). Infants with NEC had lower median birth weight than infants without NEC (p = 0.009). Infants with NEC had more late-onset sepsis (p = 0.01) and mortality before discharge (p = 0.001).The factors identified by this case-control study that increased the risk of neonatal NEC included intrauterine growth restriction and lower neonatal birth weight. The primary exposure, hypertensive disease, did not show a significantly increased risk of neonatal NEC; however, there was a nearly two-fold difference observed. Our study was underpowered to detect the observed difference.