Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation.

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

Women With a History of Preeclampsia Exhibit Accelerated Aging and Unfavorable Profiles of Senescence Markers.

BACKGROUND: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, we postulated that it is associated with accelerated aging phenotype and accumulation of comorbidities in women with a history of preeclampsia. METHODS: We included a cohort of women with a history of preeclampsia (n=40) age- and parity-matched to a group of referent women with normotensive pregnancies (n=40). Women with prior major cardiovascular events, neurological, or autoimmune conditions were excluded. We collected urine and blood samples to study markers of aging, data on multimorbidity at the time of enrollment, and prospectively followed them for events over the course of 6 years, on average. RESULTS: Women with a history of preeclampsia exhibited unfavorable aging profiles compared with referent women, including decreased urinary α-Klotho (P=0.018); increased leptin (P=0.016) and leptin/adiponectin ratio (P=0.027), and increased extracellular vesicles positive for tissue factor (P=0.025). Women with a history of preeclampsia likewise had a higher rate of comorbidities at the time of enrollment (P=0.003) and had a 4× higher risk of developing major cardiovascular events compared with referent women (P=0.003). CONCLUSIONS: Our data suggest that a history of preeclampsia is associated with accelerated aging as indicated by senescence marker differences and the accumulation of multimorbidity later in life. Targeting cellular senescence may offer novel, mechanism-based approaches for the diagnosis and treatment of adverse health outcomes in women with a history of preeclampsia.

Impact of Pregnancy on GFR Decline and Kidney Histology in Kidney Transplant Recipients.

INTRODUCTION: Women with advanced kidney disease are advised to wait until after transplant to pursue pregnancy, but the impact of pregnancy on estimated glomerular filtration rate (eGFR) decline and kidney histology is unclear. METHODS: We identified a cohort of women aged 18 to 44 years at transplant from 1996 to 2014 at our 3-site program (N = 816) and determined whether they had a pregnancy >20 weeks gestation post-transplant by chart review. Outcomes included rate of change in eGFR after pregnancy, changes in kidney histology before and after pregnancy, graft failure, and 50% reduction in eGFR. RESULTS: There were 37 women with one or more pregnancies lasting longer than 20 weeks gestation post-transplant. Comparing women with and without pregnancy post-transplant, there was a significant increase in the rate of eGFR decline after pregnancy (-2.4 ml/min per 1.73 m2 per year vs. -1.9 ml/min per 1.73 m2 per year in women with no pregnancy, P < 0.001). Pregnancy did not affect the risk of graft failure, death-censored graft failure, or 50% reduction in eGFR. CONCLUSION: Pregnancy affects the rate of eGFR decline in the allograft. Postpregnancy biopsy findings revealed an increase in vascular injury, which could be a potential mechanism. We did not find a significant increase in risk of graft failure or reduction in eGFR by 50% owing to pregnancy.

Cohort profile: the Olmsted County hypertensive disorders of pregnancy (HDP) cohort using the Rochester Epidemiology Project.

PURPOSE: The Olmsted County hypertensive disorders of pregnancy (HDP) cohort is a population-based retrospective study designed to compare the incidence of HDP on a per-pregnancy and per-woman basis and to identify associations between HDP with ageing-related diseases, as well as accumulation of multimorbidity. PARTICIPANTS: Using the Rochester Epidemiology Project (REP) medical records-linkage system, a cohort was collected consisting of women who gave birth in Olmsted County between 1976 and 1982. After exclusions, a per-pregnancy cohort of 7544 women with 9862 pregnancies between 1976 and 1982 was identified, and their delivery information was manually reviewed. A subset of these women comprised the per-woman cohort of 4322 pregnancies from 1839 women with delivery information available throughout the entirety of their childbearing years, along with decades of follow-up data available for research via the REP. FINDINGS TO DATE: By constructing both per-pregnancy and per-woman cohorts, we reported a doubling of HDP incidence rates when assessed on a per-woman basis compared with rates observed on a per-pregnancy basis. Moreover, in addition to finding that women with a history of HDP developed specific diseases at higher rates and at early ages, we also discovered that a history of HDP is associated with accelerated ageing, through accumulation of multimorbidity. FUTURE PLANS: In addition to these outcomes described above, many other potential outcomes of interest for studies of HDP can be ascertained from accessing the electronic health records (EHR) and billing systems available through the REP. These data can include all International Classification of Diseases (ICD)-9 and ICD-10 and Current Procedural Terminology coded diagnoses and procedures, healthcare utilisation, including office visits, hospitalisations and emergency room visits, and full text of the EHR that is available for chart abstraction or for natural language processing of the clinical notes.

Pregnancy, Contraception, and Menopause in Advanced Chronic Kidney Disease and Kidney Transplant.

Background: Reproductive health is an essential part of the care of women with kidney disease. However, the self-reported patient experience of reproductive issues has been underexplored. Materials and Methods: We identified a cohort of women ages 18 to 44 at the time of kidney transplant from 1996 to 2014 at our 3-site program (n = 816). We sent each woman a survey on her reproductive lifespan, characterizing features from menarche to menopause. Results: We received survey responses from 190 patients (27%). One third of respondents reported amenorrhea before transplant, and 61.5% of these women reported resumption of menses post-transplant. The average age of menopause was 45.5 years, earlier than the general population (51.3 years). There were 204 pregnancies pretransplant and 52 pregnancies post-transplant. Pregnancies post-transplant were more likely to be complicated by preeclampsia, preterm delivery, and small for gestational age babies than pregnancies that occurred >5 years before transplant. Pregnancies <5 years before transplant were similar to post-transplant pregnancies with respect to complications. Forty-two percent of women were advised to avoid pregnancy after transplant, most often by a nephrology provider. Conclusions: In our cohort of kidney transplant recipients, women report increased pregnancy-related complications post-transplant and in the 5 years before transplant, compared with pregnancies that occurred greater than 5 years before transplant. They were often counseled to avoid pregnancy altogether. Women reported a younger age of menopause relative to the general population. This should be considered when counseling patients with chronic kidney disease regarding optimal pregnancy timing.

Incidence and Long-Term Outcomes of Hypertensive Disorders of Pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are associated with increased risks for cardiovascular disease later in life. The HDP incidence is commonly assessed using diagnostic codes, which are not reliable; and typically are expressed per-pregnancy, which may underestimate the number of women with an HDP history after their reproductive years. OBJECTIVES: This study sought to determine the incidence of HDP expressed as both per-pregnancy and per-woman, and to establish their associations with future chronic conditions and multimorbidity, a measure of accelerated aging, in a population-based cohort study. METHODS: Using the Rochester Epidemiology Project medical record-linkage system, the authors identified residents of Olmsted County, Minnesota, who delivered between 1976 and 1982. The authors classified pregnancies into normotensive, gestational hypertension, pre-eclampsia, eclampsia, pre-eclampsia superimposed on chronic hypertension, and chronic hypertension using a validated electronic algorithm, and calculated the incidence of HDP both per-pregnancy and per-woman. The risk of chronic conditions between women with versus those without a history of HDP (age and parity 1:2 matched) was quantified using the hazard ratio and corresponding 95% confidence interval estimated from a Cox model. RESULTS: Among 9,862 pregnancies, we identified 719 (7.3%) with HDP and 324 (3.3%) with pre-eclampsia. The incidence of HDP and pre-eclampsia doubled when assessed on a per-woman basis: 15.3% (281 of 1,839) and 7.5% (138 of 1,839), respectively. Women with a history of HDP were at increased risk for subsequent diagnoses of stroke (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.37 to 3.76), coronary artery disease (HR: 1.89; 95% CI: 1.26 to 2.82), cardiac arrhythmias (HR: 1.62; 95% CI: 1.28 to 2.05), chronic kidney disease (HR: 2.41; 95% CI: 1.54 to 3.78), and multimorbidity (HR: 1.25; 95% CI: 1.15 to 1.35). CONCLUSIONS: The HDP population-based incidence expressed per-pregnancy underestimates the number of women affected by this condition during their reproductive years. A history of HDP confers significant increase in risks for future chronic conditions and multimorbidity.

COVID-19 and Sex Differences: Mechanisms and Biomarkers.

Men are consistently overrepresented in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and coronavirus disease 2019 (COVID-19) severe outcomes, including higher fatality rates. These differences are likely due to gender-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways related to SARS-CoV-2 infection. Several social, behavioral, and comorbid factors are implicated in the generally worse outcomes in men compared with women. Underlying biological sex differences and their effects on COVID-19 outcomes, however, have received less attention. The present review summarizes the available literature regarding proposed molecular and cellular markers of COVID-19 infection, their associations with health outcomes, and any reported modification by sex. Biological sex differences characterized by such biomarkers exist within healthy populations and also differ with age- and sex-specific conditions, such as pregnancy and menopause. In the context of COVID-19, descriptive biomarker levels are often reported by sex, but data pertaining to the effect of patient sex on the relationship between biomarkers and COVID-19 disease severity/outcomes are scarce. Such biomarkers may offer plausible explanations for the worse COVID-19 outcomes seen in men. There is the need for larger studies with sex-specific reporting and robust analyses to elucidate how sex modifies cellular and molecular pathways associated with SARS-CoV-2. This will improve interpretation of biomarkers and clinical management of COVID-19 patients by facilitating a personalized medical approach to risk stratification, prevention, and treatment.

Electronic Algorithm Is Superior to Hospital Discharge Codes for Diagnoses of Hypertensive Disorders of Pregnancy in Historical Cohorts.

OBJECTIVES: To develop and validate criteria for the retrospective diagnoses of hypertensive disorders of pregnancy that would be amenable to the development of an electronic algorithm, and to compare the accuracy of diagnoses based on both the algorithm and diagnostic codes with the gold standard, of physician-made diagnoses based on a detailed review of medical records using accepted clinical criteria. PATIENTS AND METHODS: An algorithm for hypertensive disorders of pregnancy was developed by first defining a set of criteria for retrospective diagnoses, which included relevant clinical variables and diagnosis of hypertension that required blood pressure elevations in greater than 50% of readings ("the 50% rule"). The algorithm was validated using the Rochester Epidemiology Project (Rochester, Minnesota). A stratified random sample of pregnancies and deliveries between January 1, 1976, and December 31, 1982, with the algorithm-based diagnoses was generated for review and physician-made diagnoses (normotensive, gestational hypertension, and preeclampsia), which served as the gold standard; the targeted cohort size for analysis was 25 per diagnosis category according to the gold standard. Agreements between (1) algorithm-based diagnoses and (2) diagnostic codes and the gold standard were analyzed. RESULTS: Sensitivities of the algorithm for 25 normotensive pregnancies, 25 with gestational hypertension, and 25 with preeclampsia were 100%, 88%, and 100%, respectively, and specificities were 94%, 100%, and 100%, respectively. Diagnostic code sensitivities were 96% for normotensive pregnancies, 32% for gestational hypertension, and 96% for preeclampsia, and specificities were 78%, 96%, and 88%, respectively. CONCLUSION: The electronic diagnostic algorithm was highly sensitive and specific in identifying and classifying hypertensive disorders of pregnancy and was superior to diagnostic codes.