Fitness attenuates long-term cardiovascular outcomes in women with ischemic heart disease and metabolic syndrome.

Background: The prevalence of metabolic syndrome continues to increase steadily while fitness remains relatively low. The contribution of fitness on longer-term cardiovascular outcomes and mortality in individuals with cardiovascular disease and metabolic syndrome remains unknown. Design: Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1996-2001) of women undergoing invasive coronary angiography with signs/symptoms of ischemic heart disease. Methods: Investigated the association of fitness, defined as >7METs measured by self-reported Duke Activity Status Index (DASI), and both metabolic syndrome (ATPIII criteria) and dysmetabolism (ATPIII criteria and/or treated diabetes) with long-term cardiovascular outcomes and all-cause mortality risk. Results: Among the 492 women followed for a median of 8.6 years (range 0-11 years), 19.5% were fit-metabolically healthy (reference), 14.4% fit-metabolic syndrome, 29.9% unfit-metabolically healthy, and 36.2% unfit-metabolic syndrome. Compared to reference, MACE risk was 1.52-fold higher in fit-metabolic syndrome women (HR 1.52, 95% CI 1.03-2.26) and 2.42-fold higher in unfit-metabolic syndrome women (HR 2.42, 95% CI 1.30-4.48). Compared to reference, mortality risk was 1.96-fold higher in fit-dysmetabolism (HR 1.96, 95% CI 1.29-3.00) and 3-fold higher in unfit-dysmetabolism women (HR 3.0, 95% CI 1.66-5.43). Conclusions: In a high risk cohort of women with signs/symptoms of ischemic heart disease, unfit-metabolically healthy and fit-metabolically unhealthy women were at higher risk of long-term MACE and mortality compared to fit-metabolically healthy women; and women who were unfit and metabolically unhealthy were at the highest risk. Our study demonstrates that metabolic health and fitness play an important role in long term outcomes that warrants further investigation. Registration: https://www.clinicaltrials.gov/ct2/show/NCT00000554 (NCT00000554).

Regional Variation in Hormonal and Metabolic Parameters of White and Black Women With PCOS in the United States.

CONTEXT: Ongoing research is needed to determine geo-epidemiologic differences of polycystic ovary syndrome (PCOS). OBJECTIVE: Determine hormonal and metabolic parameters of women with PCOS in 2 environments. METHODS: Prospective cohort study. SETTING: Tertiary-care based specialty clinics in Alabama and California. PATIENTS OR OTHER PARTICIPANTS: A total of 1610 women with PCOS by National Institutes of Health Criteria from 1987 to 2010. INTERVENTIONS: Interview, physical examination, laboratory studies. MAIN OUTCOMES MEASURES: Demographic data, menstrual cycle history, and hormonal and metabolic parameters were collected. Hirsutism was defined as modified Ferriman-Gallwey scores ≥4. Androgen values greater than laboratory reference ranges or >95th percentile of all values were considered elevated (hyperandrogenemia). Metabolic parameters included body mass index (BMI), waist-hip-ratio (WHR), glucose tolerance test, and homeostatic model assessment for insulin resistance (HOMA-IR) scores. RESULTS: Alabama women with PCOS were younger with a higher BMI. After adjustment for age and BMI, Alabama women with PCOS were more likely hirsute (adjusted odds ratio [aOR], 1.8; 95% CI, 1.4-2.4; P < 0.001), with elevated HOMA-IR scores (adjusted beta coefficient 3.6; 95% CI, 1.61-5.5; P < 0.001). California women with PCOS were more likely to have hyperandrogenemia (free testosterone aOR, 0.14; 95% CI, 0.11-0.18; P < 0.001; total testosterone aOR, 0.41; 95% CI, 0.33-0.51). Results were similar when stratified by White race. In Black women with PCOS, BMI and WHR did not differ between locations, yet differences in androgen profiles and metabolic dysfunction remained. CONCLUSION: Alabama women with PCOS, regardless of Black or White race, were more likely hirsute with metabolic dysfunction, whereas California women with PCOS were more likely to demonstrate hyperandrogenemia, highlighting potential environmental impacts on PCOS.

Ovarian volume as an independent marker for metabolic dysfunction in women with suspected androgen excess.

Objective: To determine whether ovarian volume (OV) alone is an independent marker for metabolic dysfunction in women with suspected androgen excess. Design: Retrospective cohort study. Setting: Tertiary academic reproductive endocrinology clinic. Patients: Women aged ≥21 years recruited/referred for symptoms related to androgen excess. Interventions: Transvaginal ovarian ultrasound, physical and medical evaluation, 2-hour 75-g oral glucose tolerance test (oGTT), and blood sampling. Main Outcome Measures: Prevalence of hyperandrogenism and metabolic dysfunction. Results: This study included 666 women, of whom 412 (61.9%) and 254 had OVs of >10 and ≤10 mL, respectively. An OV of >10 mL was associated with a higher prevalence of hirsutism (65.1% vs. 51.5%) than an OV of ≤10 mL. Polycystic ovary syndrome by the National Institutes of Health 1990 criteria was found in 67.3% and 51.4% of women with OVs of >10 and ≤10 mL, respectively. Metabolic parameters, including body mass index, waist circumference, and 1-hour insulin levels during the oGTT (odds ratio, 1.98; 95% confidence interval, 1.18-3.31), were significantly higher in women with an OV of >10 mL than in those with an OV of ≤10 mL. An OV of ≤10 mL had a 76.3% negative predictive value for hyperinsulinemia at 1 hour. Conclusions: In women with suspected androgen excess, an OV of >10 mL in at least 1 ovary is not associated with metabolic syndrome but is associated with younger age; an increased body mass index and waist circumference; a higher prevalence of hirsutism, oligoovulation, and polycystic ovary syndrome; and a higher 60-minute insulin level during the oGTT. Overall, an increased OV appears to be a good marker for hyperinsulinemia and hyperandrogenism in women suspected of having an androgen excess disorder.

Body weight and physical fitness in women with ischaemic heart disease: does physical fitness contribute to our understanding of the obesity paradox in women?

AIMS: Body mass index (BMI) defined obesity is paradoxically associated with lower all-cause mortality in patients with known cardiovascular disease. This study aims to determine the role of physical fitness in the obesity paradox in women with ischaemic heart disease (IHD). METHODS AND RESULTS: Women undergoing invasive coronary angiography with signs/symptoms of IHD in the Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1997-2001) were analysed. This study investigated the longer-term risk of major adverse cardiovascular events (MACE) and all-cause mortality associated with BMI and physical fitness measured by Duke Activity Status Index (DASI). Overweight was defined as BMl ≥25 to 30 kg/m2, obese as BMI ≥30 kg/m2, unfit as DASI scores <25, equivalent to ≤7 metabolic equivalents. Among 899 women, 18.6% were normal BMI-fit, 11.4% overweight-fit, 10.4% obese-fit, 15.3% normal BMI-unfit, 23.8% overweight-unfit, and 30.4% obese-unfit. In adjusted models compared to normal BMI-fit, normal BMI-unfit women had higher MACE risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.17-2.32; P = 0.004]; whereas obese-fit and overweight-fit women had lower risk of mortality (HR 0.60, 95% CI 0.40-0.89; P = 0.012 and HR 0.62, 95% CI 0.41-0.92; P = 0.018, respectively). CONCLUSION: To address the paradox of body weight and outcomes in women, we report for the first time that among women with signs/symptoms of IHD overweight-fit and obese-fit were at lower risk of long-term all-cause mortality; whereas normal BMI-unfit were at higher risk of MACE. Physical fitness may contribute to the obesity paradox in women, warranting future studies to better understand associations between body weight, body composition, and physical fitness to improve cardiovascular outcomes in women.

Correlation between medical management and teamwork in multidisciplinary high-fidelity obstetrics simulations.

BACKGROUND: Teamwork and communication gaps are consistently cited as contributors to adverse outcomes in obstetrics. The Critical Care in Obstetrics Course provides an innovative experience by combining brief interactive didactics with the opportunity to practice and implement the knowledge gained with hands-on simulation. Most participants have never worked together, which creates a unique environment to evaluate the importance of teamwork and communication. OBJECTIVE: This study aimed to evaluate the association between teamwork and medical management in high-fidelity critical care simulations. STUDY DESIGN: The participants were separated into multidisciplinary teams and taken through simulations, including placental abruption, hypertensive emergency, eclampsia, sepsis, cardiac arrest, venous thromboembolism, diabetic ketoacidosis, and thyroid storm. Facilitators completed a validated checklist assessment for each group's performance in medical care and teamwork. Each element was rated on a scale from 1 to 5, with 1 being unacceptable and 5 being perfect. We evaluated 5 communication measures, including the use of closed-loop communication and orientation of new team members. A Spearman correlation was used to evaluate the relationship between total medical management and total teamwork scores and specific measures of team communication. Receiver operating characteristic curves were created for total teamwork score as a predictor of good or perfect medical management. RESULTS: A total of 354 multidisciplinary teams participated in 1564 high-fidelity simulations. There was a significant correlation between medical management and teamwork and communication scores for all scenarios. The strongest correlation was for the total teamwork score for all simulations (ρ=0.84). Teamwork scores were highly predictive of medical management scores with an area under the curve of at least 0.88 for all simulations, although this was not significant for diabetic ketoacidosis. CONCLUSION: The quality of teamwork and communication correlated with the quality of clinical performance in newly formed multidisciplinary teams. This demonstrates the importance of teamwork training, with a focus on key communication tools and strategies, among medical providers to optimize the management of complex and emergent obstetrical conditions.

Implementing an inpatient postpartum depression screening, education, and referral program: a quality improvement initiative.

BACKGROUND: Perinatal mood and anxiety disorders are common and may interfere with pregnancy, delivery, and the postpartum period. Best practice includes symptom screening, patient education, and appropriate referrals; however, many hospitals struggle to identify and support perinatal mood and anxiety disorders patients. OBJECTIVE: Therefore, the Cedars-Sinai Postpartum Depression Screening, Education and Referral Program was initiated and evaluated. STUDY DESIGN: Using the Standards for QUality Improvement Reporting Excellence 2.0 guidelines, we reported outcomes (N=19,564 deliveries) from 4 interventions: (1) nurse-champion training; (2) use of the 9-item Patient Health Questionnaire-9 in the postpartum unit; (3) a series of brief in-service trainings; and (4) a 10-minute video training. We collected data including nurse feedback, screening rates, screen-positive rates, and social work consultation rates. RESULTS: The 4 interventions increased: (1) nurse-champion screening comfort and perinatal mood and anxiety disorder knowledge; (2) Patient Health Questionnaire-9 screening rates from 10% to 99% and screen-positive rates from 0.04% to 2.9%; and (3) rates of social work consultation from 1.7% to 8.4%. CONCLUSION: Quality improvement results from the first 3 years of the program suggest that 4 interventions improved screening rates, screen-positive rates, and social work consultation rates. Future work will focus on method of screening, patients at highest risk of perinatal mood and anxiety disorders, and ongoing nurse training.

Sex differences in microRNA expression in first and third trimester human placenta†.

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

High-throughput miRNA sequencing of the human placenta: expression throughout gestation.

Aim: To understand miRNA changes across gestation in healthy human placentae. This is essential before miRNAs can be used as biomarkers or prognostic indicators during pregnancy. Materials & methods: Using next-generation sequencing, we characterize the normative human placenta miRNome in first (n = 113) and third trimester (n = 47). Results & conclusion: There are 801 miRNAs expressed in both first and third trimester, including 182 with similar expression across gestation (p ≥ 0.05, fold change ≤2) and 180 significantly different (false discovery rate <0.05, fold change >2). Of placenta-specific miRNA clusters, chromosome 14 miRNA cluster decreases across gestation and chromosome 19 miRNA cluster is overall highly expressed. Chromosome 13 clusters are upregulated in first trimester. This work provides a rich atlas of healthy pregnancies to direct functional studies investigating the epigenetic differences in first and third trimester placentae.

Lay abstract The human body produces miRNAs which affect the expression of genes and proteins. This study uses next-generation sequencing to identify the miRNA profile of first and third trimester human placentae using a large cohort (n = 113 first trimester; n = 47 third trimester). All pregnancies resulted in healthy babies. We identify miRNAs with significantly different expression between first and third trimester, as well as stably expressed miRNAs. This work provides a baseline for future studies which may use miRNAs to monitor maternal­fetal health throughout pregnancy.

Mode of conception does not affect fetal or placental growth parameters or ratios in early gestation or at delivery.

PURPOSE: Ratio of fetal weight to placenta size varies by mode of conception (fertility treatments utilized) in animals. Our objective was to assess whether fertility treatments also affect these ratios in humans. METHODS: In this retrospective study, we assessed two cohorts: (a) early gestation cohort, women with singleton pregnancies who underwent first trimester vaginal ultrasound and (b) delivered cohort, women who delivered a live-born, singleton infant with placenta disposition to pathology. Crown rump length (CRL) and estimated placental volume (EPV) were calculated from first trimester ultrasound images using a validated computation. Infant birth weight (BW), pregnancy data, placental weight (PW), and placental histopathology were collected. Fetal growth-to-placental weight ratios (CRL/EPV; BW/PW) and placentas were compared by mode of conception. Linear regression was used to adjust for confounding variables. RESULTS: Two thousand one hundred seventy patients were included in the early gestation cohort and 1443 in the delivered cohort. Of the early gestation cohort (a), 85.4% were spontaneous conceptions, 5.9% Non-IVF Fertility (NIFT), and 8.7% IVF. In the delivered cohort (b), 92.4% were spontaneous, 2.1% NIFT, and 80 5.5% IVF. There were no significant differences between fetal growth-to-placental weight parameters, ratios, and neonatal birth measurements based on mode of conception. Placenta accreta was significantly higher in the patients receiving fertility treatments (1.2 versus 3.6%, p < 0.05). CONCLUSIONS: Mode of conception does not appear to influence fetal growth-to-placental weight ratios throughout gestation. In addition, findings in animal models may not always translate into human studies of infertility treatment outcomes.

Sex differences in the late first trimester human placenta transcriptome.

BACKGROUND: Development of the placenta during the late first trimester is critical to ensure normal growth and development of the fetus. Developmental differences in this window such as sex-specific variation are implicated in later placental disease states, yet gene expression at this time is poorly understood. METHODS: RNA-sequencing was performed to characterize the transcriptome of 39 first trimester human placentas using chorionic villi following genetic testing (17 females, 22 males). Gene enrichment analysis was performed to find enriched canonical pathways and gene ontologies in the first trimester. DESeq2 was used to find sexually dimorphic gene expression. Patient demographics were analyzed for sex differences in fetal weight at time of chorionic villus sampling and birth. RESULTS: RNA-sequencing analyses detected 14,250 expressed genes, with chromosome 19 contributing the greatest proportion (973/2852, 34.1% of chromosome 19 genes) and Y chromosome contributing the least (16/568, 2.8%). Several placenta-enriched genes as well as histone-coding genes were identified to be unique to the first trimester and common to both sexes. Further, we identified 58 genes with significantly different expression between males and females: 25 X-linked, 15 Y-linked, and 18 autosomal genes. Genes that escape X inactivation were highly represented (59.1%) among X-linked genes upregulated in females. Many genes differentially expressed by sex consisted of X/Y gene pairs, suggesting that dosage compensation plays a role in sex differences. These X/Y pairs had roles in parallel, ancient canonical pathways important for eukaryotic cell growth and survival: chromatin modification, transcription, splicing, and translation. CONCLUSIONS: This study is the first characterization of the late first trimester placenta transcriptome, highlighting similarities and differences among the sexes in ongoing human pregnancies resulting in live births. Sexual dimorphism may contribute to pregnancy outcomes, including fetal growth and birth weight, which was seen in our cohort, with males significantly heavier than females at birth. This transcriptome provides a basis for development of early diagnostic tests of placental function that can indicate overall pregnancy heath, fetal-maternal health, and long-term adult health.