Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

BACKGROUND: Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness. METHODS: Postpartum BP response to high salt intake was studied in women with prior preeclampsia. MR transcriptional activity was assessed in vitro in sFlt1-treated SMC by reporter assays and PCR. Preeclampsia was modeled by transient sFlt1 expression in pregnant mice. Two months post-partum, mice were exposed to high salt and then to AngII (angiotensin II) and BP and vasoconstriction were measured. RESULTS: Women exposed to preeclampsia had significantly enhanced salt sensitivity of BP verses those with a normotensive pregnancy. sFlt1 overexpression during pregnancy in mice induced elevated BP and glomerular endotheliosis, which resolved post-partum. The sFlt1 exposed post-partum mice had significantly increased BP response to 4% salt diet and to AngII infusion. In vitro, SMC-MR transcriptional activity in response to aldosterone or AngII was significantly increased after transient exposure to sFlt1 as was aldosterone-induced expression of AngII type 1 receptor. Post-partum, SMC-MR-KO mice were protected from the enhanced response to hypertensive stimuli after preeclampsia. Mechanistically, preeclampsia mice exposed to postpartum hypertensive stimuli develop enhanced aortic stiffness, microvascular myogenic tone, AngII constriction, and AngII type 1 receptor expression, all of which were prevented in SMC-MR-KO littermates. CONCLUSIONS: These data support that sFlt1-induced vascular injury during preeclampsia produces a persistent state of enhanced sensitivity of SMC-MR to activation. This contributes to postpartum hypertension in response to common stresses and supports testing of MR antagonism to mitigate the increased cardiovascular risk in women after PE.

Breastfeeding Associated with Lower Prevalence of Metabolic Syndrome in Women with Gestational Diabetes in the Very Early Postpartum Period.

OBJECTIVE: The aim of this study is to examine the association of breastfeeding with metabolic syndrome (MetS) in women with recent gestational diabetes mellitus (GDM) in the very early postpartum (PP) period. STUDY DESIGN: We performed a secondary analysis of the Balance After Baby Intervention (BABI) study which enrolled women with recent GDM. Data collected during an early (∼8 weeks) PP visit were used in this analysis. At this visit, weight, height, waist circumference (WC), blood pressure (BP), fasting plasma glucose (FPG), and lipids were obtained. MetS was classified per National Cholesterol Education Program Adult Treatment Program III (NCEP-ATP III) criteria. We defined breastfeeding as currently breastfeeding or not currently breastfeeding for the main analysis. RESULTS: Of 181 women enrolled in BABI, 178 were included in this analysis (3 excluded for missing lipids). Thirty-four percent were Hispanic. Of non-Hispanics, 31.5% were White, 18.5% Asian, and 12.9% Black/African American. The prevalence of MetS was 42.9% in women not breastfeeding versus 17.1% in women breastfeeding (p < 0.001; adjusted odds ratio [aOR] = 0.16 [95% confidence interval (CI): 0.06-0.41]). Breastfeeding women had significantly lower odds of FPG ≥100 mg/dL (aOR = 0.36 [95% CI: 0.14-0.95], p = 0.039), HDL < 50 mg/dL (aOR = 0.19 [95% CI: 0.08-0.46], p < 0.001), and triglycerides (TG) ≥ 150 mg/dL (aOR = 0.26 [95% CI: 0.10-0.66], p = 0.005). When evaluated as continuous variables, WC, FPG, and TG were significantly lower and HDL significantly higher in women breastfeeding in the very early PP period (vs. not breastfeeding). CONCLUSION: In a diverse population of women with recent GDM, there was lower prevalence of MetS in women breastfeeding compared with those not breastfeeding in the very early PP period. This study extends the findings of an association of breastfeeding with MetS previously reported at time points more remote from pregnancy to the very early PP period and to an ethnically and racially diverse population. KEY POINTS: · MetS prevalence in women with recent GDM was lower in breastfeeding than not breastfeeding women.. · FPG, HDL, WC, and TG were improved in the breastfeeding group.. · This study extends prior findings to the very early PP period and to a diverse population..

Employing a Multi-level Approach to Recruit a Representative Sample of Women with Recent Gestational Diabetes Mellitus into a Randomized Lifestyle Intervention Trial.

OBJECTIVE: The postpartum period is a window of opportunity for diabetes prevention in women with recent gestational diabetes (GDM), but recruitment for clinical trials during this period of life is a major challenge. METHODS: We adapted a social-ecologic model to develop a multi-level recruitment strategy at the macro (high or institutional level), meso (mid or provider level), and micro (individual) levels. Our goal was to recruit 100 women with recent GDM into the Balance after Baby randomized controlled trial over a 17-month period. Participants were asked to attend three in-person study visits at 6 weeks, 6, and 12 months postpartum. They were randomized into a control arm or a web-based intervention arm at the end of the baseline visit at six weeks postpartum. At the end of the recruitment period, we compared population characteristics of our enrolled subjects to the entire population of women with GDM delivering at Brigham and Women's Hospital (BWH). RESULTS: We successfully recruited 107 of 156 (69 %) women assessed for eligibility, with the majority (92) recruited during pregnancy at a mean 30 (SD ± 5) weeks of gestation, and 15 recruited postpartum, at a mean 2 (SD ± 3) weeks postpartum. 78 subjects attended the initial baseline visit, and 75 subjects were randomized into the trial at a mean 7 (SD ± 2) weeks postpartum. The recruited subjects were similar in age and race/ethnicity to the total population of 538 GDM deliveries at BWH over the 17-month recruitment period. CONCLUSIONS: Our multilevel approach allowed us to successfully meet our recruitment goal and recruit a representative sample of women with recent GDM. We believe that our most successful strategies included using a dedicated in-person recruiter, integrating recruitment into clinical flow, allowing for flexibility in recruitment, minimizing barriers to participation, and using an opt-out strategy with providers. Although the majority of women were recruited while pregnant, women recruited in the early postpartum period were more likely to present for the first study visit. Given the increased challenges of recruiting postpartum women with GDM into research studies, we believe our findings will be useful to other investigators seeking to study this population.

Accuracy of Maternal Self-Report of Recent Preeclampsia Among Healthy Women.

Background: Preeclampsia history signals a higher risk for cardiovascular disease, but its value as a risk marker relies primarily on self-report. To identify the accuracy of maternal self-reports of recent preeclampsia, we conducted a validation study among women recruited to a web-based trial. Methods: Women with preeclampsia in the past 5 years were recruited to Heart Health 4 Moms. Preeclampsia was self-reported through an online recruitment questionnaire and affirmed via phone screen. Accuracy of maternal self-report was quantified using positive predictive value (PPV) versus medical record evidence of preeclampsia using three definitions: (1) documentation of clinician diagnosis, (2) American College of Obstetricians and Gynecologists (ACOG) 2002 diagnostic criteria (gestational hypertension and proteinuria), and (3) ACOG 2013 diagnostic criteria (gestational hypertension and proteinuria or systemic symptoms). Results: Complete medical records were received for 290 women who delivered from 2011 to 2016 and were predominantly non-Hispanic White (81.7%) with a mean age of 31.2 ± 4.8 years. Mean length of recall was 13.6 ± 14.7 months. The majority of women (92.1%) had medical record evidence of preeclampsia using ≥1 of the definitions. Maternal self-report of preeclampsia was validated for 88.3% based on clinician diagnosis, 59.0% with ACOG 2002, and 65.2% with ACOG 2013. Conclusions: In this validation study of U.S. women, the majority accurately self-reported their preeclampsia diagnosis based on medical record review. A higher proportion of self-reports validated by clinician diagnosis than ACOG criteria, suggesting women remember the diagnosis given by their provider and providers may not always follow or document criteria when making a diagnosis.

Randomized Trial to Reduce Cardiovascular Risk in Women with Recent Preeclampsia.

Background: To reduce cardiovascular disease (CVD) risk, we tested an online intervention to improve healthy lifestyle for women with recent preeclampsia. Materials and Methods: We conducted a randomized controlled 9-month clinical trial, Heart Health 4 Moms (HH4M), among 151 U.S. women with preeclampsia within 5 years. Sample size was planned to detect differences of 0.5 standard deviation units in primary outcomes between study arms. Preeclampsia history was validated by medical records; women with chronic hypertension were excluded. The intervention included online educational modules, a community forum, and communication with a lifestyle coach. The control group received internet links to CVD risk reduction information. Primary outcomes were self-efficacy to eat a healthy diet and increase physical activity; change in physical in/activity; adherence to the Dietary Approaches to Stop Hypertension (DASH) diet; and knowledge of and personal control over CVD risk. Secondary outcomes were weight and blood pressure. Results: In the intervention arm, 84% of participants accessed at least one online educational module; 89% completed at least three scheduled calls with the coach. At 9 months, intervention participants reported significantly greater knowledge of CVD risk factors (corrected p = 0.01), increased self-efficacy for healthy eating (p = 0.03), and less physical inactivity than controls (p = 0.0006). The groups did not differ in sense of personal control of CVD risk factors, adherence to the DASH diet, self-efficacy for physical activity, or reported physical activity. There were no differences in secondary outcomes between groups. Conclusions: The HH4M program improved CVD risk knowledge, self-efficacy to achieve a healthy diet, and reduced physical inactivity among women with recent preeclampsia.

Treatment for 2 mo with n 3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: a randomized controlled study.

BACKGROUND: Information is lacking on the potential effect of n-3 polyunsaturated fatty acids (PUFAs) on the adipose tissue of patients with type 2 diabetes. OBJECTIVE: We evaluated whether n-3 PUFAs have additional effects on adiposity, insulin sensitivity, adipose tissue function (production of adipokines and inflammatory and atherogenic factors), and gene expression in type 2 diabetes. DESIGN: Twenty-seven women with type 2 diabetes without hypertriglyceridemia were randomly allocated in a double-blind parallel design to 2 mo of 3 g/d of either fish oil (1.8 g n-3 PUFAs) or placebo (paraffin oil). RESULTS: Although body weight and energy intake measured by use of a food diary were unchanged, total fat mass (P < 0.019) and subcutaneous adipocyte diameter (P < 0.0018) were lower in the fish oil group than in the placebo group. Insulin sensitivity was not significantly different between the 2 groups (measured by homeostasis model assessment in all patients and by euglycemic-hyperinsulinemic clamp in a subgroup of 5 patients per group). By contrast, atherogenic risk factors, including plasma triacylglycerol (P < 0.03), the ratio of triacylglycerol to HDL cholesterol (atherogenic index, P < 0.03), and plasma plasminogen activator inhibitor-1 (P < 0.01), were lower in the fish oil group than in the placebo group. In addition, a subset of inflammation-related genes was reduced in subcutaneous adipose tissue after the fish oil, but not the placebo, treatment. CONCLUSIONS: A moderate dose of n-3 PUFAs for 2 mo reduced adiposity and atherogenic markers without deterioration of insulin sensitivity in subjects with type 2 diabetes. Some adipose tissue inflammation-related genes were also reduced. These beneficial effects could be linked to morphologic and inflammatory changes in adipose tissue. This trial was registered at clinicaltrials.gov as NCT0037.

Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study.

OBJECTIVES: This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity. STUDY DESIGN AND MAIN OUTCOME MEASURES: This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009-2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (±1year) and delivery date (±3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors. RESULTS: Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/m2, 95% CI: 1.07-1.3, p=0.001) were identified as significant risk factors in multivariate analysis. CONCLUSIONS: We identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE.

Improving the postpartum care of women with a recent history of preeclampsia: a focus group study.

OBJECTIVE: Women with prior preeclampsia are at increased risk of cardiovascular disease (CVD). This study investigated barriers and facilitators toward learning about this link and engaging in lifestyle modifications to reduce this risk. METHODS: Four focus groups were held with 14 women within 6 months of a preeclamptic pregnancy. RESULTS: Participants were unaware of the link between preeclampsia and CVD, suggested improvements to provider-patient communication, and discussed the benefits of social support and online tracking (weight, blood pressure) in making lifestyle modifications. CONCLUSIONS: Solutions offered may improve efforts to modify lifestyle and communication between providers and women about this link.