l-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia.

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new-onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcomes. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal l-citrulline supplementation on pregnancy-specific vascular dysfunction in the male C57BL/6J × female C57BL/6J C1q-/- preeclampsia-like mouse model. l-Citrulline is a nonessential amino acid that is converted to l-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO)-mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams was supplemented with l-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 mo of age. Main findings show that l-citrulline reduced blood pressure, increased vascular glycocalyx volume, and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of l-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 mo of age. l-Citrulline-mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, l-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health, which may have translational implications for improved maternal cardiovascular health.

Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum.

Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q-/- model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q-/- male mice to model a preeclampsia-like pregnancy ("PE-like"), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q-/- model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.

Nitric oxide signaling in pregnancy and preeclampsia.

While the etiology of preeclampsia continues to be elucidated, it is clear that preeclampsia is a complex obstetrical syndrome associated with maternal vascular dysfunction within which impairments in nitric oxide (NO) signaling likely play a key role in driving disease progression and severity. The goal of this review is to present the available evidence for maladaptations in NO and NO signaling in pregnancies complicated by preeclampsia. After a brief overview of preeclampsia, a review of the available evidence for NO and NO signaling adaptations in normal, uncomplicated pregnancy is given to lay a foundation for changes driven by preeclampsia. Next, current evidence for maladaptations of NO and NO signaling in preeclampsia is reviewed. Finally, a brief summary of NO-focused treatments for preeclampsia prevention is discussed. Considering preeclampsia is a syndrome solely occurring among pregnant women, this review focuses on NO signaling in clinical studies, with supplementary evidence from animal studies added when necessary.

Extracellular matrix regenerative graft attenuates the negative impact of polypropylene prolapse mesh on vagina in rhesus macaque.

BACKGROUND: The use of wide pore lightweight polypropylene mesh to improve anatomical outcomes in the surgical repair of prolapse has been hampered by mesh complications. One of the prototype prolapse meshes has been found to negatively impact the vagina by inducing a decrease in smooth muscle volume and contractility and the degradation of key structural proteins (collagen and elastin), resulting in vaginal degeneration. Recently, bioscaffolds derived from extracellular matrix have been used to mediate tissue regeneration and have been widely adopted in tissue engineering applications. OBJECTIVE: Here we aimed to: (1) define whether augmentation of a polypropylene prolapse mesh with an extracellular matrix regenerative graft in a primate sacrocolpopexy model could mitigate the degenerative changes; and (2) determine the impact of the extracellular matrix graft on vagina when implanted alone. STUDY DESIGN: A polypropylene-extracellular matrix composite graft (n = 9) and a 6-layered extracellular matrix graft alone (n = 8) were implanted in 17 middle-aged parous rhesus macaques via sacrocolpopexy and compared to historical data obtained from sham (n = 12) and the polypropylene mesh (n = 12) implanted by the same method. Vaginal function was measured in passive (ball-burst test) and active (smooth muscle contractility) mechanical tests. Vaginal histomorphologic/biochemical assessments included hematoxylin-eosin and trichrome staining, immunofluorescent labeling of α-smooth muscle actin and apoptotic cells, measurement of total collagen, collagen subtypes (ratio III/I), mature elastin, and sulfated glycosaminoglycans. Statistical analyses included 1-way analysis of variance, Kruskal-Wallis, and appropriate post-hoc tests. RESULTS: The host inflammatory response in the composite mesh-implanted vagina was reduced compared to that following implantation with the polypropylene mesh alone. The increase in apoptotic cells observed with the polypropylene mesh was blunted in the composite (overall P < .001). Passive mechanical testing showed inferior parameters for both polypropylene mesh alone and the composite compared to sham whereas the contractility and thickness of smooth muscle layer in the composite were improved with a value similar to sham, which was distinct from the decreases observed with polypropylene mesh alone. Biochemically, the composite had similar mature elastin content, sulfated glycosaminoglycan content, and collagen subtype III/I ratio but lower total collagen content when compared to sham (P = .011). Multilayered extracellular matrix graft alone showed overall comparable values to sham in aspects of the biomechanical, histomorphologic, or biochemical endpoints of the vagina. The increased collagen subtype ratio III/I with the extracellular matrix graft alone (P = .033 compared to sham) is consistent with an ongoing active remodeling response. CONCLUSION: Mesh augmentation with a regenerative extracellular matrix graft attenuated the negative impact of polypropylene mesh on the vagina. Application of the extracellular matrix graft alone had no measurable negative effects suggesting that the benefits of this extracellular matrix graft occur when used without a permanent material. Future studies will focus on understanding mechanisms.

Urinary cortisol and depression in early pregnancy: role of adiposity and race.

BACKGROUND: Depression before and during pregnancy is associated with adverse birth outcomes including low birth weight and preterm birth. Abnormal maternal cortisol has been hypothesized as one mediator between depression and adverse birth outcomes. The relationship between cortisol and depression in pregnancy is exhibited most strongly in the African American population, and most studies have focused either on circulating or placental levels of cortisol. The utility of urinary cortisol in early pregnancy related to depression and adiposity has not been investigated. METHODS: Twenty-five pregnant African American women identified by the Edinburgh Depression Scale as having depression were investigated and matched by body mass index (BMI), age, race, and infant birth weight centile to non-depressed subjects. Maternal urine and plasma cortisol in early pregnancy were quantified and investigated in relation to depression and adiposity. RESULTS: Morning urine cortisol levels tracked positively with plasma cortisol (r(2) = 0.25, p < 0.001). However, no differences were observed in either urinary or plasma cortisol between depressed and non-depressed pregnant women. Plasma cortisol was significantly negatively associated with several measures of maternal adiposity including percent body fat (r(2) = -0.10, p < 0.05), however this relationship was present only in the non-depressed women. In a post-hoc analysis, non-depressed non-obese women were found to have significantly higher cortisol levels compared to women with depression, obesity or both (p < 0.05). CONCLUSIONS: Depressed pregnant women and non-depressed obese pregnant women evidence atypical cortisol levels compared to non-depressed non-obese pregnant women. Plasma cortisol in early pregnancy is negatively associated with measures of maternal adiposity. Atypical low circulating maternal cortisol among depressed (lean and obese) and non-depressed obese pregnant African American women may indicate hypothalamic-pituitary axis dysfunction in early pregnancy.

Arginine and asymmetric dimethylarginine in pregnant women with major depression.

OBJECTIVE: Depression has been associated with vascular dysfunction, which may be of particular relevance in pregnancy. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-arginine play a critical role in vascular function. The objective of this study was to investigate differences in ADMA, SDMA, and L-arginine among pregnant women with major depression compared with pregnant women without depression. METHODS: A case-control study was conducted in 21 depressed pregnant women and 42 matched controls. Maternal plasma ADMA, SDMA, and L-arginine were quantified, as well as C-reactive protein and urine excretion of ADMA, SDMA, L-arginine, and Arginase I. RESULTS: Plasma L-arginine and ADMA levels were significantly lower in the first trimester in women with depression (mean [standard deviation = 37.0 [9.2] and 0.298 [0.06] µM, respectively) compared with matched controls (42.1 [11.4] and 0.336 [0.08] µM, p = .004 and p = .002, respectively) and across pregnancies (p < .001 both). Depressed pregnant women had higher levels of plasma C-reactive protein (7.5 [3.7] versus 5.1 [4.0] µg/ml, p = .027), but no differences in urine excretion of ADMA, SDMA, or L-arginine, or plasma levels of Arginase I (p > .10). CONCLUSIONS: Pregnant women with depression show lower plasma levels of L-arginine and ADMA. These differences are not explained by urinary excretion or Arginase I levels. The mechanism responsible for the observed differences in depressed pregnant women requires further research.

An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype.

RATIONALE: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (Fe(NO)). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. OBJECTIVES: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. METHODS: Cross-sectional study of participants from the Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes. MEASUREMENTS AND MAIN RESULTS: Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 µM, [interquartile range (IQR), 0.35-0.7] compared with early onset, 0.37 µM [IQR, 0.29-0.59], P = 0.01) and lower median plasma l-arginine (late onset, 52.3 [IQR, 43-61] compared with early onset, 51 µM [IQR 39-66]; P = 0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late- (r = -0.4, P = 0.0006) in contrast to the early-onset phenotype (r = -0.2, P = 0.07). Although Fe(NO) was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. CONCLUSIONS: In late-onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to Fe(NO). In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.

Modeling Normal Mouse Uterine Contraction and Placental Perfusion with Non-invasive Longitudinal Dynamic Contrast Enhancement MRI.

The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. Non-invasive imaging that can longitudinally probe murine placental health in vivo are critical to understanding placental development throughout pregnancy. We developed advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. We developed a dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) pipeline combined with advanced image process methods to model uterine contraction and placental perfusion dynamics. Our novel imaging pipeline uses subcutaneous administration of gadolinium for steepest-slope based perfusion evaluation. This enables non-invasive longitudinal monitoring. Additionally, we advance the placental perfusion chamber paradigm with a novel physiologically-based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and continuing remodeling throughout gestation. Lastly, using optic flow to quantify placental motions arisen from uterine contractions in conjunction with time-frequency analysis, we demonstrated that the placenta exhibited asymmetric contractile motion.

Modeling normal mouse uterine contraction and placental perfusion with non-invasive longitudinal dynamic contrast enhancement MRI.

BACKGROUND: The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. OBJECTIVE: Our goal is to create a non-invasive preclinical imaging pipeline that can longitudinally probe murine placental health in vivo. We use advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. METHODOLOGY: We implement dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) and analysis pipeline to quantify uterine contraction and placental perfusion dynamics. We use optic flow and time-frequency analysis to quantify and characterize contraction-related placental motion. Our novel imaging and analysis pipeline uses subcutaneous administration of gadolinium for steepest slope-based perfusion evaluation, enabling non-invasive longitudinal monitoring. RESULTS: We demonstrate that the placenta exhibits spatially asymmetric contractile motion that develops from E14.5 to E17.5. Additionally, we see that placental perfusion, perfusion delivery rate, and substrate delivery all increase from E14.5 to E17.5, with the High Perfusion Chamber (HPC) leading the placental changes that occur from E14.5 to E17.5. DISCUSSION: We advance the placental perfusion chamber paradigm with a novel, physiologically based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and remodeling throughout gestation. CONCLUSION: Our pipeline enables the non-invasive, longitudinal assessment of multiple placenta functions from a single imaging session. Our pipeline serves as a key toolbox for advancing research in mouse models of placental disease and disorder.

Pre-pregnancy stress induces maternal vascular dysfunction during pregnancy and postpartum.

An estimated 20% of women suffer from a stress-related mood disorder including depression and anxiety during and after pregnancy, making these disorders among the most common complications of pregnancy. These stress-related disorders are associated with adverse pregnancy outcomes including gestational hypertension and preeclampsia, which are associated with poor cardiometabolic health postpartum. Despite these associations, the direct impact of stress and related disorders on maternal vascular health, and contributing mechanisms, remain understudied. The aim of this study was to investigate the effect of pre-pregnancy stress on maternal vascular outcomes in a BALB/c mouse model of chronic unpredictable stress. Maternal blood pressure and ex-vivo vascular function were investigated during pregnancy and postpartum. Offspring characteristics were assessed at the end of pregnancy and postpartum. Main findings show that pre-pregnancy stress exposure increased blood pressure during mid and late pregnancy and impaired ex vivo vascular function at the end of pregnancy. These effects persisted into the postpartum period, suggesting a long-term effect of stress on maternal vascular health, which appear to be partially attributable to disruptions in nitric oxide (NO) pathway signaling. These data suggest exposure to stress and related disorders, even prior to pregnancy, can contribute to vascular complications during pregnancy and postpartum.

Haptoglobin phenotype, angiogenic factors, and preeclampsia risk.

OBJECTIVE: We sought to determine whether haptoglobin (Hp) phenotype is related to preeclampsia risk, or to plasma concentrations of soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF). STUDY DESIGN: Hp phenotype was retrospectively determined in primiparous women with uncomplicated pregnancies (n = 309), gestational hypertension (n = 215), and preeclampsia (n = 249). Phenotype was assessed by peroxidase staining following native polyacrylamide gel electrophoresis of hemoglobin-supplemented serum. RESULTS: Compared with Hp 1-1, Hp 2-1 was associated with a significantly increased risk of preeclampsia (odds ratio, 2.11; 95% confidence interval, 1.07-4.18) and term preeclampsia (odds ratio, 2.45; 95% confidence interval, 1.07-5.83) in Caucasian women. Hp phenotype was not associated with preeclampsia risk in African Americans. Preeclamptic women had higher plasma sEng and sFlt-1, and lower PlGF, than control subjects. sEng, sFlt-1, and PlGF did not differ among women of different Hp phenotypes. CONCLUSION: Hp 2-1 is associated with higher preeclampsia risk in primiparous Caucasian women.

An exploratory factor analysis of nutritional biomarkers associated with major depression in pregnancy.

OBJECTIVE: Major depressive disorder (MDD) during pregnancy increases the risk of adverse maternal and infant outcomes. Maternal nutritional status may be a modifiable risk factor for antenatal depression. We evaluated the association between patterns in mid-pregnancy nutritional biomarkers and MDD. DESIGN: Prospective cohort study. SETTING: Pittsburgh, Pennsylvania, USA. SUBJECTS: Women who enrolled at ≤20 weeks' gestation and had a diagnosis of MDD made with the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) at 20-, 30- and 36-week study visits. A total of 135 women contributed 345 person-visits. Non-fasting blood drawn at enrolment was assayed for red cell essential fatty acids, plasma folate, homocysteine and ascorbic acid; serum 25-hydroxyvitamin D, retinol, vitamin E, carotenoids, ferritin and soluble transferrin receptors. Nutritional biomarkers were entered into principal components analysis. RESULTS: Three factors emerged: Factor 1, Essential Fatty Acids; Factor 2, Micronutrients; and Factor 3, Carotenoids. MDD was prevalent in 21·5 % of women. In longitudinal multivariable logistic models, there was no association between the Essential Fatty Acids or Micronutrients pattern and MDD either before or after adjustment for employment, education or pre-pregnancy BMI. In unadjusted analysis, women with factor scores for Carotenoids in the middle and upper tertiles were 60 % less likely than women in the bottom tertile to have MDD during pregnancy, but after adjustment for confounders the associations were no longer statistically significant. CONCLUSIONS: While meaningful patterns were derived using nutritional biomarkers, significant associations with MDD were not observed in multivariable adjusted analyses. Larger, more diverse samples are needed to understand nutrition-depression relationships during pregnancy.

Small extracellular vesicles from plasma of women with preeclampsia increase myogenic tone and decrease endothelium-dependent relaxation of mouse mesenteric arteries.

Preeclampsia (PE) is a common syndrome of pregnancy, characterized by new-onset hypertension and proteinuria after gestational week 20, or new onset of hypertension and significant end-organ dysfunction. In the worst cases, it can threaten the survival of both mother and baby. Extracellular vesicles (EVs) are lipid-bilayer nanoparticles released from cells. They are involved in cell-cell communication and transport of diverse cargo molecules. Small extracellular vesicles (sEVs, exosomes) are defined by their size and biogenesis within the endocytic compartment of the cell or reverse budding of the plasma membrane. The function of circulating gestational EVs, released from maternal organs or the placenta, remains to be explored. Here, we focused on sEVs that circulate in the maternal blood in the third trimester of human pregnancy and hypothesized that sEVs from pregnant women with PE play a role in regulation of vessel tone. When compared to sEVs from women with uncomplicated pregnancies, ex vivo exposure of isolated mouse mesenteric arteries to sEVs purified from the plasma of pregnant women with PE led to constriction in response to intraluminal pressure. This effect was not observed using microvesicles from the plasma of women with PE or using PE plasma that was depleted of EVs. Blood vessels exposed to sEVs from women with PE were also more resistant to methacholine-stimulated relaxation. Immunofluorescence microscopy confirmed the presence of sEVs within the vessel wall. Together, these data support the notion that circulating sEVs from pregnant women play a role in the regulation of arterial tone.

Caffeine and insulin resistance in pregnancy.

Outside pregnancy, acute caffeine consumption is associated with insulin resistance. We investigated if during pregnancy plasma concentrations of caffeine and its metabolite, paraxanthine, were associated with insulin resistance. Caffeine, paraxanthine, glucose, and insulin were measured and insulin resistance estimated by homeostasis model assessment (HOMA) in banked samples from 251 fasting subjects at mean gestational age of 20.3 ± 2.0 weeks. Analysis of covariance and adjusted logistic regression were performed. Most (96.4%) women had caffeine and/or paraxanthine present. Caffeine concentrations in the upper two quartiles (>266 ng/mL) were associated with threefold higher odds of having higher insulin resistance estimated by log HOMA ≥75th percentile (third quartile odds ratio [OR], 3.02; 95% confidence interval [CI]: 1.21 to 7.54 and fourth quartile OR, 2.95; 95% CI: 1.19 to 7.31). Paraxanthine concentrations in the upper quartile (>392 ng/mL) were also associated with threefold higher odds of having higher insulin resistance (OR, 3.04; 95% CI: 1.28 to 7.25). Adjusted mean HOMA in the first caffeine-to-paraxanthine ratio quartile was 1.5 ± 2.2 versus 1.3 ± 2.3 in the fourth quartile ( P < 0.01). Both high caffeine and paraxanthine concentrations were associated with insulin resistance, but slow versus fast metabolism did not make an important difference.

Go Red for Women Strategically Focused Research Network: Summary of Findings and Network Outcomes.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

Vascular endothelial growth factor and breast cancer risk.

Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case-control study of 407 pre- and postmenopausal women (n = 203 cases, n = 204 controls). Logistic regression was used to model the breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy (HT) use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/ml) than controls (291.4 pg/ml; p = 0.21). In a multivariable model, the odds of breast cancer was 37% higher for women with VEGF levels > or =314.2 pg/ml compared to those with levels below 314.2 pg/ml, albeit not significantly (p = 0.16). There was no interaction between VEGF and menopausal status (p = 0.52). In this case-control study, VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.

Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia.

BACKGROUND: Cigarette smoking during pregnancy is paradoxically associated with a reduced risk of developing preeclampsia. Both smoking and preeclampsia are associated with alterations in circulating angiogenic factors. The objective of this study was to investigate the relationship between cigarette smoking and the angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnant women with and without preeclampsia. METHODS: Plasma sFlt-1, PlGF, and cotinine were measured using enzyme-linked immunosorbent assay in 125 women with uncomplicated pregnancies (controls) and 58 women with preeclampsia. RESULTS: In uncomplicated pregnancies, maternal sFlt-1 concentrations were lower in smokers compared to nonsmokers (779.6 (487.5-1,140.8) vs. 1,116.5 (793.6-1,905.2) pg/ml, P < 0.005). Preeclamptic women who smoked also demonstrated a trend toward lower concentrations of sFlt-1 compared to nonsmokers (3,423.0 (2,183.4-5,689.0) vs. 5,504.9 (3,418.0-6,361.3) pg/ml, P = 0.07). Maternal PlGF concentrations were higher in smokers with uncomplicated pregnancies (398.4 (165.2-621.7) vs. 191.4 (104.6-446.8) pg/ml); however, this was not a statistically significant difference (P = 0.07). PlGF concentrations were not different in preeclamptic smokers compared to nonsmokers. The sFlt/PlGF ratio was significantly lower in smokers with uncomplicated pregnancies, but not in smokers with preeclampsia compared to nonsmokers. CONCLUSIONS: Cigarette smoking is associated with lower maternal sFlt-1 concentrations during pregnancy and preeclampsia. On the basis of these data, cigarette smoke exposure may decrease the risk of preeclampsia in part by moderating the anti-angiogenic phenotype observed in the syndrome.

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants.

OBJECTIVE: The purpose of this study was to investigate maternal plasma concentrations of asymmetric dimethylarginine (ADMA) in mid pregnancy and at the time of disease in women who experience preeclampsia, compared with women with uncomplicated pregnancies and women with small-for-gestational-age infants. STUDY DESIGN: Plasma samples were collected at mid-pregnancy and at the time of delivery from 31 women with uncomplicated pregnancies, from 12 women with small-for-gestational-age infants, and from 15 women with preeclampsia. ADMA and L-arginine concentrations were measured using high-pressure liquid chromatography. RESULTS: Maternal ADMA concentrations were elevated at mid pregnancy and remained elevated at delivery in women who later experienced preeclampsia (0.45 +/- 0.09 micromol/L) compared with women with uncomplicated pregnancies (0.34 +/- 0.08 micromol/L; P < .01) and with women with small-for-gestational-age infants (0.33 +/- 0.06 micromol/L; P < .01). CONCLUSION: Maternal ADMA concentrations are higher in mid pregnancy in women who experience preeclampsia, compared with women with uncomplicated pregnancies and small-for-gestational-age infants. Elevated ADMA concentration before clinical onset of preeclampsia suggests a role of this nitric oxide synthase inhibitor in the pathophysiologic condition of preeclampsia.

A comparison of circulating TNF-alpha in obese and lean women with and without preeclampsia.

OBJECTIVES: We hypothesized that TNF-alpha would be higher in obese versus lean women with preeclampsia. METHODS: Total plasma TNF-alpha was measured in a nested case-control study of 123 nulliparous lean and obese control women and women with preeclampsia. RESULTS: Adjusted mean TNF-alpha concentrations were 0.97 +/- 0.11 (pg/mL +/- SEM) in lean controls, 1.01 +/- 0.10 in obese controls, 1.43 +/- 0.11 in lean women with preeclampsia and 1.16 +/- 0.11 in obese women with preeclampsia. Pregnancy outcome was the single predictor of TNF-alpha concentration in the general linear regression model (p = 0.04). CONCLUSION: TNF-alpha concentration was higher in preeclampsia compared with control subjects. Obesity was not associated with higher TNF-alpha concentrations in either preeclampsia or control subjects.

Maternal Outcomes Associated With Lower Range Stage 1 Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes in healthy, nulliparous women classified with stage 1 hypertension under the revised American College of Cardiology and American Heart Association Guidelines and to evaluate the effects of low-dose aspirin on maternal and neonatal outcomes in this population. METHODS: We conducted a secondary analysis of data from a multicenter randomized, double-blind, placebo-controlled trial of low-dose aspirin for prevention of preeclampsia in nulliparous, low-risk women recruited between 13 and 25 weeks of gestation. Of the 3,134 nulliparous women enrolled in the original study, 2,947 women with singleton pregnancies and without missing data were included in this analysis. Blood pressure was measured at enrollment between 13 and 25 weeks of gestation and outcomes were adjudicated from the medical record. RESULTS: One hundred sixty-four participants were identified with lower range stage 1 hypertension (5.6%), systolic blood pressure 130-135 mm Hg, diastolic blood pressure 80-85 mm Hg, or both by the new American College of Cardiology-American Heart Association guidelines. Within the placebo group (n=1,482), women with stage 1 hypertension had a significantly increased incidence of preeclampsia compared with normotensive women, 15.3% (15/98) vs 5.4% (75/1,384) (relative risk 2.66, 95% CI 1.56-4.54, P<.001). Moreover, women with stage 1 hypertension had an increased incidence of gestational diabetes mellitus (6.1% vs 2.5%, P=.03) and more indicated preterm deliveries (4.2% vs 1.1%, P=.01). Comparing women with stage 1 hypertension and normotensive women receiving low-dose aspirin during pregnancy (n=1,465), no differences in rates of preeclampsia (7.6% vs 4.4%, respectively, P=.2), gestational diabetes mellitus, or indicated preterm deliveries were observed. Rates of placenta abruption, small for gestational age, and spontaneous preterm birth did not differ significantly between groups. CONCLUSION: Application of the new American College of Cardiology-American Heart Association guidelines in a pregnant population identifies a cohort of women who are at increased risk for preeclampsia, gestational diabetes mellitus, and preterm birth.