Adrienne Schonberg

Sildenafil Increases Uterine Blood Flow in Nonpregnant Nulliparous Women

This study investigated the effect of sildenafil on uterine volumetric blood flow (UVF) and vascular impedance in nonpregnant, nulliparous women. Fifteen women were randomized in a double-blind fashion to receive either placebo or sildenafil (25 or 100 mg) during the luteal phase of the menstrual cycle. Color Doppler ultrasound of both uterine arteries was performed at baseline and at 1 and 3 hours postdosing to calculate resistance index (RI) and UVF. Those who received sildenafil significantly increased UVF and decreased RI over the 3-hour monitoring period. When UVF responses to sildenafil were examined as a function of baseline UVF, a significant increase in UVF was observed in only those participants with higher baseline UVF. Overall, women in the luteal phase demonstrated a significant increase in UVF in response to sildenafil. However, this increase appears to be directly associated with basal UVF.

The Relationship of Plasma Volume, Sympathetic Tone, and Proinflammatory Cytokines in Young Healthy Nonpregnant Women

Objective. Preeclampsia has been associated with elevated proinflammatory markers, increased sympathetic activity, and decreased plasma volume (PV). We hypothesized that these associations would be identified in women prior to a first pregnancy. Methods. We studied 76 healthy nulligravid participants measuring the proinflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Plasma volume was measured in supine position and corrected for body mass index (BMI). We examined supine plasma levels of epinephrine and norepinephrine and blood pressure response to Valsalva maneuver to quantify sympathetic activation. We then examined the association of PV and sympathetic activity with proinflammatory cytokines with P < .05 accepted for significance. Results. CRP was significantly increased in participants with lowest PV/BMI quartile when compared to middle 2 quartiles and highest quartile (analysis of variance [ANOVA], P = .037). We found no significant association of PV/BMI with either IL-6 or TNF-α. Both plasma epinephrine concentration (r = .29, P = .02) and the late phase II (phase II_L) blood pressure response to Valsalva maneuver (r = .44, P < .0001) were associated with serum IL-6 concentrations. Conclusions. Low PV is associated with increased CRP levels and increased sympathetic tone is linked to elevated IL-6 concentration in young nonpregnant women. These findings represent elements of a nonpregnancy phenotype that parallels the findings observed in preeclampsia and in women at risk for ischemic cardiovascular disease. This suggests that the relationships observed during preeclampsia, which have been associated with placental pathology, may predate pregnancy and be independent of placental activity.

Relationship between Prepregnancy and Early Pregnancy Uterine Blood Flow and Resistance Index

We evaluated the relationship between prepregnancy and early pregnancy uterine blood flow (UBF) and resistance index (RI). Nineteen nulliparous participants were studied during cycle day 8 + 4, and early pregnancy (13.4 + 1.6 weeks). Color Doppler ultrasound of both uterine arteries and maternal heart was performed to calculate uterine RI, volumetric UBF, and cardiac output (CO), respectively. We observed a strong negative association of uterine RI with prepregnancy UBF (r = —.82, P < .001) that weakened, but remained significant in early pregnancy (r =—.48, P = .04). Prepregnancy uterine index (UBF/CO) was significantly associated with early pregnancy uterine index; r = .48, P = .04). There was also a trend associating prepregnancy and early pregnancy volumetric UBF (r = .44, P = .068). Prepregnancy UBF may be a determinant of early pregnancy UBF and UBF may have independent value as a predictor of adverse pregnancy outcome.

Pulse Pressure and Arterial Compliance Prior to Pregnancy and the Development of Complicated Hypertension during Pregnancy

We examined the relationship between prepregnant pulse pressure (PP), mean arterial pressure (MAP), cardiac output (CO)/PP, a measure of arterial compliance, and development of complicated hypertension (CH) during pregnancy with the goal of identifying a potential predictor of CH. Twenty nulliparous participants were studied before pregnancy; 17 had normal pregnancies (control; CTL) and 3 CH. Blood pressure monitoring was performed using tonometry. Cardiac output was determined by Doppler echocardiograph. Data are expressed as mean ± SD. Prepregnant PP was significantly higher in CH participants (CH: 58.3 ± 6.3, CTL: 46.2 ± 1.7 mm Hg; P = .02). Cardiac output /pulse pressure was significantly lower in CH participants (CH: 6.9 ± 1.8, CTL: 10.6 ± 2.8; P = .04). Mean arterial pressure was not significantly different. Increased PP before pregnancy may suggest increased risk for CH. With accurate prediction of CH before pregnancy, initiation of preventative measures could begin earlier, either prior to or in early pregnancy, potentially increasing preventative efficacy and decreasing CH.

Uterine Blood Flow Response to Alpha-Adrenergic Blockade in Nulligravid Women of Reproductive Age

Objective: Elevated uterine artery resistance has been associated with the development of preeclampsia. We sought to determine if the human uterine arterial circulation was more sensitive to alpha-adrenergic blockade than a control vascular bed. Methods: We studied 38 healthy nulliparous women during the follicular phase of the menstrual cycle. Arteriolized venous blood was measured for plasma epinephrine and norepinephrine. Doppler ultrasound of the uterine and upper extremity radial artery was performed before and after intravenous administration of phentolamine. Heart rate and volumetric flow were calculated. Data are presented as means ± SD. Results: Mean heart rate before and after administration of phentolamine was 63 ± 11 and 68 ± 12 beats per minute (7.5% increase, P < .001). Mean radial artery blood flow before and after administration of phentolamine was 4.6 ± 4.7 mL/min and 5.8 ± 5.9 mL/min (19.9% increase, P = .071). Mean uterine blood flow before and administraiton of phentolamine was 15.4 ± 10.1 mL/min and 27.3 ± 17.5 mL/min (43.7% increase, P < .001). The uterine response (43.7% increase) and radial response (19.9% increase) were significantly different (P < .001). The increase in uterine blood flow after phentolamine administration was linked with resting norepinephrine (r = 0.394, P = .063). Conclusion: We found evidence that uterine alpha-adrenergic tone is more sensitive to blockade by phentolamine than upper extremity radial circulation. This provides evidence for a differential responsiveness and sensitivity to alpha-adrenergic blockade in different vascular beds. We theorize that the increased adrenergic tone associated with preeclampsia may contribute disproportionately to decreased uterine blood flow.

Platelet activation, sympathetic tone, and plasma volume in nulligravid women of reproductive age.

OBJECTIVE: Preeclampsia is associated with increased platelet activation, increased sympathetic activity, and decreased plasma volume. We sought to estimate the relationship of plasma volume, sympathetic activity, or both to platelet activation in nonpregnant nulligravid women. METHODS: We studied 37 healthy nulligravid subjects during the follicular phase of the menstrual cycle. After intravenous access was obtained, subjects rested in the supine position for 15 minutes. Blood was drawn without venous constriction for measurement of plasma catecholamines (epinephrine and norepinephrine) and complete blood count. Antigenic markers of platelet activation, CD63 and CD61-CD14 (platelet-monocyte aggregates), were measured with flow cytometry. Plasma volume was estimated in the supine position by using Evans blue dye and is expressed in milliliters and corrected for body mass index (BMI). We compared data from the lowest plasma volume/BMI quartile with the 2 middle quartiles combined and with the upper quartile. Data are expressed as mean ± standard deviation. P < .05 was considered significant. RESULTS: Subjects were aged 26.5 ± 5.0 years, BMI was 24.0 ± 3.0 kg/m2, and plasma volume was 2,685 ± 429 mL. We identified no significant relationship of platelet concentration to plasma volume/BMI between quartile groups (P = .944). However, there was a significant difference between quartiles for %CD63 expression (P = .013) and for CD61/CD14 expression (P = .018), with the lowest quartile demonstrating elevated platelet activation. CONCLUSIONS: We found evidence that enhanced platelet activation is associated with reduced plasma volume, but not with plasma catecholamine concentrations. There was no association of platelet concentration with reduced plasma volume. We speculate that elements of the clinical syndrome of preeclampsia coexist as a subclinical phenotype before pregnancy. LEVEL OF EVIDENCE: II-3