Immune Markers, Blood Pressure Severity, and Cardiac Remodeling 1 to 2 Years After Hypertensive Disorders of Pregnancy.

Background Cardiovascular dysfunction and hypertension can persist postpartum following hypertensive disorders of pregnancy (HDPs). This study hypothesized that activin A, proinflammatory markers and concentric remodeling by echo would be higher 1-2 years postpartum following HDP with persistent hypertension compared to HDP with normalized blood pressure (BP). We further hypothesized correlations between biomarkers with BP and echocardiographic indices. Methods and Results This study enrolled participants with HDPs but no prepregnancy hypertension followed 1 to 2 years after delivery. Activin A and inflammatory cytokines, BP, and echocardiograms were obtained. Biomarker concentrations and echocardiographic parameters were compared between HDP with and without persistent hypertension. Individuals with persistent hypertension at a mean of 1.6 years postpartum had significantly higher activin A concentrations (median[interquartile range 25-75] 230.6 [196.0-260.9] versus 175.3 pg/mL [164.3-188.4]; P<0.01), more concentric left ventricular concentric remodeling (relative wall thickness >0.42, 48% versus 7%; P<0.01), and worse peak left atrial strain (33.4% versus 39.3%; P<0.05) as compared with those whose BP normalized. Higher activin A and interleukin-6 concentrations correlated with higher systolic (activin A: r=0.43, P=0.01) and diastolic BP (activin A: r=0.58, P<0.01; interleukin-6: r=0.36; P<0.05), as well as greater left ventricular thickness (activin A and interventricular septal thickness: r=0.41, interleukin-6 and interventricular septal thickness: r=0.36; both P<0.05). Conclusions Individuals with HDPs and persistent hypertension had significantly higher activin A and greater concentric remodeling compared with those with HDPs and normalized BP at 1 to 2 years postpartum. Activin A was positively correlated with both BP and echocardiographic indices (left ventricular thickness), suggesting overlapping processes between persistent hypertension and cardiac remodeling.

Post-partum myocardial ischemia due to intramuscular methylergonovine-induced coronary vasospasm: case report.

BACKGROUND: Methylergonovine is a vasoconstrictive agent historically used as a provocative agent in the lab for coronary vasospasm; it is also a first line uterotonic agent for management of postpartum hemorrhage. CASE PRESENTATION: A 29-year-old female with history of smoking and idiopathic thrombocytopenia received intramuscular methylergonovine after delivery of twins for intrauterine hemorrhage management. Subsequently, she had episodes of chest pain with high sensitivity Troponin I elevation to 1509 ng/L with accompanying septal T wave inversions, decreased left ventricular ejection fraction to 49% and basal septal wall hypokinesis. Computed tomography (CT) coronary angiogram showed patent coronary arteries and no coronary arterial dissection. The patient was conservatively managed with aspirin and metoprolol, and on follow up had fully recovered left ventricular function with resolution of wall motion abnormalities. Given this, coronary vasospasm due to intramuscular methylergonovine is the most likely cause of patient's chest pain and associated myocardial ischemia. CONCLUSIONS: Intramuscular, intrauterine, intravenous, and even oral methylergonovine can rarely cause coronary vasospasm leading to myocardial ischemia. Cardiologists caring for postpartum patients should be aware of these potential lethal complications; prompt identification and administration of sublingual nitroglycerin can prevent severe complications of arrythmias, heart block, or cardiac arrest.

A Possible Mechanism of Action of 17α-Hydroxyprogesterone Caproate: Enhanced IL-10 Production.

OBJECTIVE: The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. STUDY DESIGN: We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. RESULTS: In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. CONCLUSION: In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. KEY POINTS: · 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..

Neighborhood disadvantage and the racial disparity in postpartum hypertension.

BACKGROUND: Postpartum hypertension is the leading cause of postpartum readmission and has long-lasting cardiovascular effects. Black patients have higher incidence rates of hypertensive disorders after delivery and subsequent severe maternal morbidity. Neighborhood advantage, a marker of social determinants of health, has not been studied concerning postpartum hypertension. Moreover, the interplay between race and neighborhood advantage and their effect on postpartum hypertension have not been previously explored. OBJECTIVE: This study aimed to evaluate the association between neighborhood-level social determinants of health and postpartum hypertension and explore whether these factors explain previously documented racial disparities. STUDY DESIGN: This study included a retrospective cohort of people enrolled in a remote monitoring program of postpartum hypertension at the time of delivery within 1 health network from March 2019 to September 2021. Patients were eligible for enrollment after a diagnosis of hypertensive disorder during pregnancy or delivery. We further limited the cohort to self-reported Black and White patients with blood pressures recorded at 3 weeks and 6 weeks postpartum. The neighborhood advantage for each person at the time of delivery was classified using the area deprivation index, an accepted surrogate of social determinants of health and our primary exposure. The secondary exposure was self-reported race. Study outcomes of interest were hypertensive status (stage 1 hypertension: ≥130 to 139/80 to 89 mm Hg; stage 2 hypertension: ≥140/90 mm Hg) at 3 and 6 weeks after delivery. In addition, hypertensive status by neighborhood area deprivation index using logistic regression was molded. In secondary analyses, a case-control cohort matched on the area deprivation index was created, and conditional logistic regression was used to evaluate race. Finally, mixed-effects models modeling hypertension by race and clustering within the area deprivation index were used. RESULTS: Of 4193 people enrolled, 2722 were Black or White and had blood pressure data recorded at 3 weeks after delivery, and 1126 had blood pressure data recorded at 6 weeks after delivery. After accounting for prenatal body mass index, smoking status, type of hypertension, and antihypertensives prescribed at discharge, persons living in the most disadvantaged neighborhoods were twice as likely (adjusted odds ratio, 2.03; 95% confidence interval, 1.53-2.69) to develop stage 2 hypertension at 21 days after delivery and 1.67 times more likely (95% confidence interval, 1.06-2.64) to develop stage 2 hypertension at 6 weeks after delivery than persons living in the most advantaged neighborhoods. Both associations were attenuated after adjusting for race. When people with stage 2 hypertension were matched on area deprivation index with normotensive counterparts, Black patients were still 3 to 4 times more likely to develop stage 2 hypertension at 3 (adjusted odds ratio, 3.00; 95% confidence interval, 1.95-4.63) and 6 (adjusted odds ratio, 4.61; 95% confidence interval, 2.05-10.36) weeks after delivery. This association remained after clustering within a neighborhood at 3 (adjusted odds ratio, 3.12; 95% confidence interval, 2.41-4.06) and 6 (adjusted odds ratio, 2.99; 95% confidence interval, 1.96-4.54) weeks after delivery. There was no significant difference in stage 1 hypertension. CONCLUSION: Neighborhood advantage was associated with the development of persistent hypertension at 3 and 6 weeks after delivery. This association did not explain the racial disparity in sustained high blood pressure.

Infective Endocarditis in Pregnancy: A Contemporary Cohort.

OBJECTIVE: Pregnancy-related infective endocarditis (IE) caries a high risk of morbidity and mortality. With increasing intravenous drug abuse (IVDA) amid the opioid epidemic, the risk factor profile may be shifting. In this case series, we aimed to describe risk factors and outcomes for peripartum IE in a contemporary cohort. STUDY DESIGN: We identified patients with IE diagnosed during pregnancy or up to 6 weeks' postpartum from 2015 through 2018 at a single tertiary care center. We abstracted detailed medical history and clinical outcome measures from the electronic medical record. The diagnosis of IE was supported by the modified Duke Criteria. RESULTS: Nine patients had peripartum IE: eight (89%) with a history of IVDA, one with an indwelling central venous catheter (11%), and one with prior IE (11%). None had preexisting congenital or valvular heart disease. Six (67%) had comorbid hepatitis C. Eight cases (89%) had gram-positive cocci with vegetations involving the tricuspid valve (56%) and both mitral and tricuspid valves (22%). Major complications included shock (33%), mechanical ventilation (44%), septic emboli (67%), and noncardiac abscesses (33%). Two patients underwent valve surgery, and there were two cases of postpartum maternal mortality (22%), one from septic shock and one from intracerebral hemorrhage. While four patients (44%) delivered preterm (average gestational age 35 weeks), most delivered vaginally (89%) with only one requiring an emergent caesarean section. There was no fetal mortality, although three newborns (43%) required admission to the neonatal intensive care unit. Two patients were initiated on medication-assisted treatment for opioid use disorder. Consultants included infectious disease, cardiology, cardiac surgery, maternal-fetal medicine, and psychiatry. CONCLUSION: These findings confirm that IVDA is a growing risk factor for pregnancy-related IE. Peripartum IE carries a high risk of complications, including maternal mortality, and warrants management with a multidisciplinary care team at a tertiary center. KEY POINTS: · Intravenous drug use was the most common risk factor for IE in pregnancy.. · IE in pregnancy carries a high morbidity and mortality with complications including septic emboli, septic shock, and need for mechanical ventilation.. · A multidisciplinary team approach can assure the best possible maternal and fetal outcomes..

Assessment of Racial Disparities in Aspirin Prophylaxis for Preeclampsia Prevention.

OBJECTIVE: Low-dose aspirin is recommended for preeclampsia prevention among women with high-risk conditions, including chronic hypertension. Black women have higher rates of hypertensive disorders of pregnancy, and whether this is related to disparities in aspirin prophylaxis is unknown. We investigated the relationship between race and counseling/prescription and uptake of aspirin among a cohort of women with chronic hypertension. STUDY DESIGN: This is a single-institution, retrospective cohort study of women with chronic hypertension who delivered between 2016 and 2018. Medical record review was performed to assess counseling/prescription of aspirin prophylaxis and self-reported uptake. Self-reported uptake was determined by mention in the provider's notes or by inclusion in the medication reconciliation system. Demographic and obstetric outcome data were compared by self-reported race (Black vs. all other races) in univariate analysis. Multivariable logistic regression analysis was performed to evaluate the association between race and aspirin adherence. RESULTS: We included 872 women: 361 (41.4%) Black women and 511 (58.6%) white or other race women. Overall, 567 (65.0%) women were counseled and/or given a prescription for aspirin, and 411 (72.4%) of those women reported uptake. Black women were equally likely to be counseled and/or prescribed aspirin compared with all other races (67.3 vs. 63.4%; p = 0.7). However, Black women were less likely to report uptake of aspirin (63.8 vs. 79.0%; p < 0.001). After adjustment for total prenatal visits and tobacco use, Black race was associated with an adjusted odds ratio of 0.53 (95% confidence interval: 0.36-0.78) for uptake of aspirin. CONCLUSION: In our cohort, recommendation for aspirin prophylaxis was suboptimal in all groups, reaching only 65% of eligible women. Black women were equally likely as women of other races to receive counseling about aspirin, but rates of uptake were lower. Our findings suggest that counseling and prescription of aspirin alone in high-risk Black women are not sufficient for utilization of this intervention. KEY POINTS: · Rates of counseling about aspirin prophylaxis for preeclampsia did not vary by race.. · Black women had lower rates of uptake of aspirin compared with women of other races.. · Counseling about aspirin was inadequate in general, reaching only 65% of eligible women..

Association of N-Terminal Pro-Brain Natriuretic Peptide Concentration in Early Pregnancy With Development of Hypertensive Disorders of Pregnancy and Future Hypertension.

IMPORTANCE: Hypertensive disorders of pregnancy are associated with future cardiovascular disease, perhaps because of subclinical cardiac dysfunction before pregnancy leading to impaired adaptation to pregnancy. Natriuretic peptides are promising biomarkers for detecting subclinical cardiac dysfunction outside of pregnancy. OBJECTIVE: To investigate whether higher concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) in early pregnancy would be associated with hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study, a prospective multicenter observational study. A total of 4103 nulliparous women with complete data and no prepregnancy hypertension or diabetes who were treated at 8 clinical sites were included. Women were followed up with for 2 to 7 years after pregnancy. Data were collected from October 2010 to October 2017, and data were analyzed from August 2020 to November 2021. EXPOSURES: NT-proBNP concentration, measured using an electrochemiluminescence immunoassay from a first-trimester blood sample. MAIN OUTCOMES AND MEASURES: Hypertensive disorders of pregnancy and incident hypertension (systolic blood pressure of 130 mm Hg or diastolic blood pressure of 80 mm Hg or use of antihypertensive agents) at follow-up visit. RESULTS: A total of 4103 women met inclusion criteria; the mean (SD) age was 27.0 (5.6) years. Among these women, 909 (22.2%) had an adverse pregnancy outcome, and 817 (19.9%) had hypertension at the follow-up visit. Higher NT-proBNP concentrations were associated with a lower risk of hypertensive disorders of pregnancy (adjusted odds ratio per doubling, 0.81; 95% CI, 0.73-0.91), which persisted after adjustment for age, self-reported race and ethnicity, early-pregnancy body mass index, smoking, and aspirin use. Similarly, higher NT-proBNP concentration in early pregnancy was also associated with a lower risk of incident hypertension 2 to 7 years after delivery (adjusted odds ratio per doubling, 0.84; 95% CI, 0.77-0.93), an association that persisted after controlling for confounders, including hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE: In this cohort study, higher NT-proBNP concentrations in early pregnancy were associated with a lower risk of hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. These findings suggest that normal early-pregnancy cardiovascular physiology, as assessed by NT-proBNP concentration, may provide biologic insights into both pregnancy outcome and cardiovascular disease risk.

Risk of hypertension and abnormal biomarkers in the first year postpartum associated with hypertensive disorders of pregnancy among overweight and obese women.

OBJECTIVES: Hypertension and obesity are common cardiometabolic risk factors in reproductive age women. The association of hypertensive disorders of pregnancy with later-life cardiovascular disease is well-established, however, it is unknown how obesity and hypertensive disorders of pregnancy converge to accelerate development of hypertension in the postpartum period. The aim of this study was to characterize rates of sustained hypertension at one year postpartum using the new American Heart Association/American College of Cardiology Guidelines among overweight and obese women with a normotensive pregnancy or hypertensive disorder of pregnancy. STUDY DESIGN: 315 early pregnant women were enrolled prospectively and followed up to 12 months after delivery (mean 7.0 ±â€¯1.8 months). At a postpartum research visit, we measured blood pressure and collected blood samples to measure cystatin C and high sensitivity C-reactive protein. RESULTS: A total of 254 women had a normotensive pregnancy, 39 had gestational hypertension (12.4%) and 22 had preeclampsia (7.0%). 91 women had hypertension at the postpartum study visit (28.9%). After adjustment for maternal age, BMI, lactation and time postpartum, preeclampsia was associated with an aOR 2.35 (95%CI 1.63-3.41) of development of sustained hypertension and an aOR 3.23 (95%CI 1.56-6.68) of hypertension with abnormal biomarkers compared to women with normotensive pregnancies. CONCLUSIONS: We demonstrate a high prevalence of hypertension and abnormal biomarkers associated with hypertensive disorders of pregnancy among overweight and obese women. Our findings support the need for structured follow up and risk reduction in overweight and obese women with hypertensive disorders of pregnancy as early as the first year postpartum.

Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity.

Most current methods of gene delivery for primary cultured hippocampal neurons are limited by toxicity, transient expression, the use of immature neurons and/or low efficiency. We performed a direct comparison of seven serotypes of adeno-associated virus (AAV) vectors for genetic manipulation of primary cultured neurons in vitro. Serotypes 1, 2, 7, 8 and 9 mediated highly efficient, nontoxic, stable long-term gene expression in cultured cortical and hippocampal neurons aged 0-4 weeks in vitro; serotypes 5 and 6 were associated with toxicity at high doses. AAV1 transduced over 90% of all cells with approximately 80% of the transduced cells being neurons. The method was readily adapted to a high-throughput format to demonstrate neurotrophin-mediated neuroprotection from glutamate toxicity in cultured neurons at 2 weeks in vitro. These vectors should prove highly useful for efficient overexpression or downregulation of genes in primary neuronal cultures at any developmental stage.