Differential effects of renin-angiotensine-aldosteron system inhibition, sympathoinhibition and low sodium diet on blood pressure in women with a history of preeclampsia: A double-blind, placebo-controlled cross-over trial (the PALM study).

Current guidelines lack sufficient evidence to recommend a specific blood pressure lowering strategy to prevent cardiovascular disease after preeclampsia. We conducted a double-blind cross-over trial to identify the most potent antihypertensive strategy: renin-angiotensin-aldosterone system (RAAS) inhibition (losartan), sympathoinhibition (moxonidine), low sodium diet and placebo (n = 10). Due to low inclusion rate our study stopped prematurely. Initiatory analyses showed no significant effect of antihypertensive strategy on office blood pressure and 24-hour blood pressure. However, nocturnal dipping was significantly higher on RAAS inhibition and low sodium diet compared to placebo and sympathoinhibition. Optimal cardiovascular prevention after preeclampsia should be further explored.

Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy.

Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by proinflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether proinflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast before exploring potential regulatory mechanisms. There was increased immunoreactivity of heat shock 70-kDa protein 5, also known as 78-kDa glucose regulated protein, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared with normotensive controls. Treating EVT-like JEG-3 and HTR8/SVneo cells with ER stress inducers (tunicamycin and thapsigargin) suppressed MMP2 mRNA and protein expression, secretion, and activity and reduced their invasiveness. A cocktail of proinflammatory cytokines (IL-1ß, tumor necrosis factor-α, and interferon-γ) suppressed MMP-2 activity in JEG-3 cells and was accompanied by activation of the PKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2A (EIF2A) arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which proinflammatory cytokines may modulate trophoblast invasion through ER stress pathways.

Routine testing of Mycoplasma genitalium and Trichomonas vaginalis.

BACKGROUND: Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) are common sexual transmitted infections (STI). However, most STI screening programmes do not include routinely detection of these pathogens. Consequently, epidemiological data about MG and TV in the general population is lacking. The current study aims to give insight into the prevalence of both infections, thereby guiding decisions whether testing for these pathogens should be included routinely. METHODS: Between February 2013 and August 2015, all samples sent to the laboratory of Diakonessenhuis Utrecht for STI testing (i.e. testing for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG)) were additionally examined for the presence of MG and TV by means of a laboratory-developed RT-PCR. Samples were collected by our hospital or by regional general practitioners. RESULTS: A total of 5628 PCR's were evaluated. In 7.5%, one or more STI were detected. CT was found in 5% and MG was positive in 1.9%. NG was detected in 0.5% and TV was detected in 0.6% of the samples. CT was found more often in primary care than in hospital setting (9.7% vs. 3.0%, p < .05). The same was shown for NG (1.1% vs. 0.2%, p < .05). More men than women were positive for CT (11.2% vs. 3.8%, p < .05) and NG (1.4% vs. 0.3%, p < .05). CONCLUSION: MG is more prevalent than NG and TV in a regional Dutch population. Furthermore, TV is equally common as NG. Based on our prevalence data, including MG and TV in STI testing protocols should be considered in the future.

Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study.

BACKGROUND: Women with a history of placental bed disorders, including preeclampsia and intrauterine growth restriction have an increased long-term risk of cardiovascular disease (CVD). Further, similarities exist between atherosclerosis and abnormalities observed in placental bed spiral arteries in pregnancies affected by preeclampsia and intrauterine growth restriction, such as acute atherosis and defective remodeling. This suggests a common pathophysiological pathway underlying both disorders. OBJECTIVES: The aim of this study was to investigate vascular and inflammatory lesions in the placental bed of women with preeclampsia and normal pregnancy using a systematic approach to characterize lesions of the placental bed, and relate spiral artery pathology to postpartum CVD risk assessment. METHODS: Placental bed punch biopsies were performed following caesarean section and systematically studied to assess vascular pathology, arterial remodeling, and the presence of CD3, CD56, and CD68 cells. In addition, levels of modifiable CVD risk factors were assessed immediately postpartum. RESULTS: We found fewer spiral arteries with complete remodeling in women with preeclampsia than in the control group (21 vs. 68%; P = 0.008). Further, women with preeclampsia showed less presence of CD3 cells in both the decidua and the myometrium. Preliminary findings of CVD risk factor assessment postpartum suggest a correlation between acute atherosis and higher triglyceride and low-density lipoprotein cholesterol levels. CONCLUSION: Systematic study of vascular pathology in uterine spiral artery biopsy samples in relation to CVD risk factors provides valuable insight into the link between cardiovascular health and placental bed disorders.

Morphological and molecular changes in the murine placenta exposed to normobaric hypoxia throughout pregnancy.

Chronic hypoxia is a common complication of pregnancy, arising through malperfusion of the placenta or pregnancy at high altitude. The present study investigated the effects of hypoxia on the growth of the placenta, which is the organ that interfaces between the mother and her fetus. Mice were housed in an hypoxic environment for the whole of gestation. An atmosphere of 13% oxygen induced fetal growth restriction (1182 ± 9 mg, n = 90 vs. 1044 ± 11 mg, n = 62, P < 0.05) but enhanced placental weight (907 ± 11 mg, n = 90 vs. 998 ± 15 mg, n = 62,P < 0.05). Stereological analyses revealed an increase in the volume of maternal blood spaces in the placenta, consistent with increased flow. At the molecular level, we observed activation of the protein kinase B (Akt)-mechanistic target of rapamycin growth and proliferation pathway. Chronic hypoxia also triggered mild endoplasmic reticulum stress, a conserved homeostatic response that mediates translational arrest through phosphorylation of eukaryotic initiation factor 2 subunit α. Surprisingly, although subunits of the mitochondrial electron transport chain complexes were reduced at the protein level, there was no evidence of intracellular energy depletion. Finally, we demonstrated sex-specific placental responses to chronic hypoxia. Placentas from male fetuses were heavier (1082 ± 2 mg, n = 30 vs. 928 ± 2 mg, n = 34, P < 0.05) and less susceptible to hypoxia-induced oxidative stress than those from females. Their capacity to adapt may explain why male fetuses were significantly less growth restricted at embryonic day 18.5 than their female counterparts. These findings are consistent with the concept that male fetuses are more aggressive with respect to their nutrient demands, which may place them at greater risk of adverse outcomes under limiting conditions.

Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension.

Observational studies have shown an increased lifetime risk of cardiovascular disease (CVD) in women who experienced a hypertensive disorder in pregnancy. This risk is related to the severity of the pregnancy-related hypertensive disease and gestational age at onset. However, it has not been investigated whether these differences in CVD risk factors are already present at postpartum cardiovascular screening. We evaluated postpartum differences in CVD risk factors in 3 subgroups of patients with a history of hypertensive pregnancy. We compared the prevalence of common CVD risk factors postpartum among 448 women with previous early-onset preeclampsia, 76 women with previous late-onset preeclampsia, and 224 women with previous pregnancy-induced hypertension. Women with previous early-onset preeclampsia were compared with women with late-onset preeclampsia and pregnancy-induced hypertension and had significantly higher fasting blood glucose (5.29 versus 4.80 and 4.83 mmol/L), insulin (9.12 versus 6.31 and 6.7 uIU/L), triglycerides (1.32 versus 1.02 and 0.97 mmol/L), and total cholesterol (5.14 versus 4.73 and 4.73 mmol/L). Almost half of the early-onset preeclampsia women had developed hypertension, as opposed to 39% and 25% of women in the pregnancy-induced hypertension and late-onset preeclampsia groups, respectively. Our data show differences in the prevalence of common modifiable CVD risk factors postpartum and suggest that prevention strategies should be stratified according to severity and gestational age of onset for the hypertensive disorders of pregnancy.

Maternal cardiovascular risk profile after placental abruption.

The prevalence of premature cardiovascular diseases (CVD) is increased in women with a history of maternal placental syndromes, including pregnancy-associated hypertensive disorders (eg, preeclampsia), fetal growth restriction, and placental abruption. Whereas previous studies have shown a high prevalence of CVD risk factors after pregnancies complicated by preeclampsia, this has not been studied for women with a history of placental abruption. To explore the association of placental abruption with CVD risk factors after delivery, we compared 75 women with a history of placental abruption with a control group of 79 women with uneventful pregnancies at 6 to 9 months postpartum for the presence of common CVD risk factors. In a subanalysis, data were stratified according to the presence or absence of concomitant hypertensive disease and further adjusted for potential confounders. Women with previous placental abruption had significantly higher mean systolic blood pressure, body-mass index, fasting blood glucose, C-reactive protein, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol as compared with controls with only uneventful pregnancies. In the subanalysis, all differences remained significant for women with a history of placental abruption only (ie, without concomitant gestational hypertension), except for the associations with low-density lipoprotein-cholesterol and diastolic and systolic blood pressure. Most likely, the identified CVD risk factors predispose to placental abruption and development of premature CVD later in life.

Genomic aberrations relate early and advanced stage ovarian cancer.

BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.