Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Risk of necrotizing enterocolitis and feeding interventions for preterm infants with abnormal umbilical artery Doppler.

Infants exposed to absent or reversed end-diastolic flow (ARE DF) in utero may be at an increased risk of developing necrotizing enterocolitis (NEC). This article reviews placental function and the development of ARE DF. Studies examining the relationship between AREDF and NEC are reviewed, yet research remains inconclusive regarding this relationship. Recent studies reveal that early minimal enteral feeding does not increase the incidence of NEC in infants with AREDF. Initiation and advancement of enteral feedings should be monitored closely in this subset of the neonatal intensive care unit (NICU) population.

Folic acid is positively associated with uteroplacental vascular resistance: the Generation R study.

BACKGROUND AND AIMS: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study. METHODS AND RESULTS: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [ß -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [ß -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [ß -0.06, 95% CI -0.1, -0.03] and late pregnancy [ß -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [ß -0.02, 95% CI -0.04, -0.001] and late pregnancy [ß -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories. CONCLUSION: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders.

Doppler velocimetry of the uterine, umbilical and fetal middle cerebral arteries in pregnant women undergoing tocolysis with oral nifedipine.

OBJECTIVES: To evaluate Doppler velocimetry (resistance index (RI) and peak systolic velocity (PSV)) in the maternal-fetal circulation before and 5 and 24 h after tocolysis with oral nifedipine. METHODS: This was a prospective, observational, analytic cohort study performed in 47 pregnant women undergoing nifedipine tocolysis, each subject acting as her own control. Doppler assessment of uterine, umbilical and fetal middle cerebral (MCA) arteries was performed before and 5 and 24 h after an initial 20-mg sublingual dose, which was repeated twice at 20-min intervals if contractions failed to diminish. The maintenance dose consisted of 20 mg orally every 6 h for 24 h up to a total of 100-120 mg nifedipine. We analyzed whether there was a time effect and compared values at the different time-points. RESULTS: The MCA-RI had decreased significantly after 24 h of tocolysis (0 h = 0.85; 5 h = 0.85; 24 h = 0.81; P = 0.001), with no differences in uterine or umbilical arteries or in the MCA to umbilical artery ratio. The MCA-PSV had reduced significantly after 5 h (0 h = 41.5 cm/s; 5 h = 34.7 cm/s; P = 0.001), returning close to baseline levels between 5 and 24 h. The PSV increased significantly between 5 and 24 h in the right uterine artery (5 h = 55.1 cm/s; 24 h = 65.0 cm/s; P = 0.037) and in the umbilical artery (5 h = 28.4 cm/s; 24 h = 33.1 cm/s; P = 0.038). CONCLUSIONS: Nifedipine tocolysis is associated with a reduction in RI in the MCA but not in the uterine or umbilical arteries, a reduction in PSV in the MCA after 5 h but returning to baseline within 24 h, and an increase in PSV between 5 and 24 h in the umbilical and right uterine arteries.

Effects of oral L-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor.

OBJECTIVE: The objective of the study was the estimation of the influence of oral supplementation with low-dose l-arginine on feto-placental circulation in women with threatened preterm labor. STUDY DESIGN: Oral administration of 3g of L-arginine daily or placebo as a supplement to standard tocolytic therapy was tried in 70 women with threatened preterm delivery, randomly assigned to the L-arginine (n=37) or placebo (n=33) groups. Twenty-five and 20 completed the study, respectively. Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as pregnancy outcome and biochemical markers of nitric oxide synthesis (plasma amino acid and nitrite/nitrate levels, as well as 24 h nitrite/nitrate excretion with urine) were estimated. RESULTS: Starting from the second week of therapy, the UA PI values were significantly lower in the L-arginine group than in the placebo group. Moreover, treatment with L-arginine caused a significant increase in MCA PI and cerebro-placental ratio (CPR) values. The changes in feto-placental circulation in the L-arginine group were not associated with any signs of increased nitric oxide synthesis. CONCLUSION: Oral supplementation with low doses of L-arginine changed feto-placental blood flow distribution in patients with threatened preterm labor. The exact mechanism of L-arginine action on feto-placental circulation requires further investigation.

Influence of preeclampsia or maternal intake of omega-3 fatty acids on the vasoactive effect of prostaglandin F-two-alpha in human umbilical arteries.

The vasoactive effect of prostaglandin F(2alpha) (PGF(2alpha)) was studied in in vitro perfused human umbilical arteries following maternal dietary supplementation with omega-3 fatty acids or in pregnancies complicated by a moderate degree of preeclampsia. In most preparations PGF(2alpha) induced a biphasic pressure response with a transient dilatation followed by a constrictory response. The pressure increase was significant in both groups, but no significant differences in the constrictory response or in the proportions of preparations displaying dilatatory responses were observed when compared to appropriate control groups. In conclusion, neither preeclampsia nor dietary supplementation with cod-liver oil had any significant effect on the vasoactive response to PGF(2alpha) in umbilical cord arteries.

Alterations of placental vascular function in asthmatic pregnancies.

Asthma during pregnancy is associated with low-birthweight neonates at term but the mechanisms that cause this outcome are presently unknown. Changes in placental vascular function resulting from asthma or its treatment could contribute to altered fetal growth. We have prospectively followed women with asthma and a control group of women without asthma during their pregnancies, classified them based on asthma severity and glucocorticoid intake, and monitored fetal development and placental blood flow using Doppler ultrasound at 18 and 30 wk gestation. The placentae from these women were collected after delivery and vascular responses to dilator and constrictor agonists assessed using an in vitro placental perfusion method. At 18 wk gestation, umbilical artery flow velocity waveforms were significantly reduced in the moderate and severe asthmatic groups and in those women using high-dose inhaled glucocorticoid for the treatment of their asthma (ANOVA, p < 0.05). However, at 30 wk gestation there were no significant differences in umbilical artery flow velocity between control and asthmatic women (ANOVA, p > 0.05). Corticotropin-releasing hormone (CRH), a potent vasodilator that acts via the nitric oxide pathway, caused a dose-dependent vasodilatory response in all placentae in vitro. However, CRH-induced dilation was significantly reduced in moderate and severe asthmatics (ANOVA, p < 0.05). Vasoconstrictor responses to potassium chloride and prostaglandin F(2alpha) were reduced in placentae from moderate and severe asthmatic women (ANOVA, p < 0.05). These studies demonstrate significant differences in placental vascular function in pregnancies complicated by asthma, which may relate directly to the asthma or be a consequence of the associated glucocorticoid treatment. These changes in vascular function in asthmatic pregnancies may contribute to the low-birthweight outcome observed in this condition.

[Effect of Salvia Miltiorrhiza injection on umbilical artery hemodynamics during fetal distress in ewe].

OBJECTIVE: To study the effect of Salvia Miltiorrhiza injection (SMI) on umbilical artery hemodynamics during fetal distress in ewe. METHODS: Intrauterine surgery were performed at 116-125 gestational days in 3 pregnancy sheep for insertion of vascular catheters at abdominal aorta from femoral artery and for implantation of a electromagnetic flowmetre probe around umbilical artery. Gelatin microsphere injection to abdominal aorta through vascular catheter for obstruction of placental-fetal circulation. 2 ml of SMI was used 6 times(2 times each sheep), and the signs of umbilical artery blood flow and wave forms of fetal abdominal aorta blood pressure were recorded before and after injections of gelatin microsphere or SMI. The fast Fourier translation (FFT) was used to turn signs in time domain into powers spectral of input impedance in frequency domain for resistance and characteristic impedance of umbilical artery. RESULTS: After the SMI was injected into fetal abdominal aorta, the resistance of umbilical artery was significantly reduced (P < 0.05), and the changes of resistance was significantly relative with the resistance before SMI injected (r = -0.85, P < 0.001). But there were no significantly different impedance between before and after SMI treatment (P > 0.05). CONCLUSIONS: The SMI to fetal abdominal aorta can decrease umbilical artery blood flow resistance and the changes of resistance was significantly relative to that before SMI treatment.

Cerebral and umbilical vascular resistance response to vibroacoustic stimulation in growth-restricted fetuses.

OBJECTIVE: To test the hypothesis that after vibroacoustic stimulation the ratio between cerebral vascular and umbilical vascular resistance in the growth-restricted fetus is different from that in the normal fetus. METHODS: The pulsatility index (PI) of the middle cerebral artery and that of the umbilical artery (UA) were measured by pulsed Doppler velocimetry in 30 normal and 14 growth-restricted fetuses before and after vibroacoustic stimulation. The ratios of cerebral PI to UA PI and the changes in PI after vibroacoustic stimulation were calculated. Comparisons were made using the Wilcoxon rank-sum test or signed-rank test. The statistical power of the study was 80%. RESULTS: Mean (+/- standard deviation) cerebral PI values before vibroacoustic stimulation (1.50 +/- 0.29) in normals and 1.29 +/- 0.26 in the fetal growth restriction [FGR] group) and UA PI values (1.00 +/- 0.18 in normals and 1.15 +/- 0.24 in the FGR group) were significantly different between groups (P < .04) and significantly decreased after vibroacoustic stimulation (P < .05). Although the cerebral to UA PI ratios (1.50 +/- 0.38 in normals and 1.13 +/- 0.33 in the FGR group) were significantly different between groups (P < .008), the values remained the same after vibroacoustic stimulation (P = .39 and .80, respectively). In all fetuses the fetal heart rate accelerated after vibroacoustic stimulation. CONCLUSION: Cerebral vascular resistance was lower and umbilical vascular resistance higher in the growth-restricted fetuses than in normals. The vascular resistance response after vibroacoustic stimulation in the growth-restricted fetus was not significantly different from the response of the normal fetus, suggesting preservation of regulation of resistance.

[Antenatal screening for fetal well being by pulsed Doppler velocimetry].

A pulsed Doppler screening study was performed on pregnant women to investigate the ability of the test to detect adverse pregnancy outcome by following two methods. The waveforms were analyzed by calculating the resistance index (RI). Method 1.: longitudinal study: Blood flow velocity in the umbilical artery (UA) was recorded at 23, 28, 32, and 35 weeks' gestation in 726 pregnancies. Method 2.: cross-sectional study with FAS: Blood flow velocity in the UA and fetal middle cerebral artery (MCA) was recorded before and after fetal acoustic stimulation (FAS) at 35 weeks' gestation in 525 pregnancies. Result 1.: As UA-RI decreases continuously with gestational age, there was a linear correlation between them. The 726 cases were classified into three groups according to the UA-RI value. The UA-RI of the control group (n = 698) never reached mean + 2SD. The UA-RI of the +2.5D group (n = 4) increased with gestational age and was over mean +2.5SD at the last measurement. The +2SD group (n = 24) remained. There was a significant adverse pregnancy outcome in the +2.5SD group as judged by intrauterine growth retardation (SGA) (+2.5SD; 75%, +2SD; 17%, control; 10%), fetal distress (+2.5SD; 75%, +2SD; 5%; control; 9%) and pregnancy induced hypertension (+2.5SD; 75%, +2SD; 23%, control; 8%). Result 2.: The normal ranges of UA-RI and MCA-RI were calculated at 35 weeks' gestation, both before and after FAS, and women with UA-RI > +2SD or MCA-RI < -2SD were considered as abnormal.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of nifedipine and dipyridamole on the Doppler blood flow waveforms of umbilical and uterine arteries in hypertensive pregnant women.

In a study of 45 hypertensive pregnant women, the systolic velocity/diastolic velocity ratio and pulsatility index of the umbilical and uterine arteries showed good correlation with the maternal blood pressure, and they appeared to provide a good parameter for the fetoplacental condition. Using the pulse Doppler method, we studied the effects of the antihypertensive agent nifedipine and of dipyridamole (an agent used to treat proteinuria) on the blood flow of the umbilical and uterine arteries in 16 hypertensive pregnant women. The results proved that both drugs caused a decrease in the vascular resistance of the umbilical artery and suggested that they increased the blood flow volume of this artery and were useful in the treatment of hypertension during pregnancy.

The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term.

Twenty patients with preeclampsia at a gestational age of 26 to 35 weeks were treated with oral nifedipine until delivery. The mean oral daily dose was 45.1 +/- 11 mg/day (range, 40 to 80 mg/day). Fetal aorta, internal carotid artery, umbilical artery, and uteroplacental Doppler flow velocity waveforms were recorded before treatment and then serially. The mean nifedipine concentration at the time of the Doppler studies was 60.3 ng/ml (range, 10 to 90 ng/ml). The use of nifedipine therapy was associated with a significant decrease in both maternal systolic blood pressure (baseline, 154 to 135 mm Hg, p less than 0.001) and diastolic blood pressure (baseline, 100 to 88 mm Hg, p less than 0.001). However, there was no significant difference in the resistance index between baseline and postnifedipine Doppler studies in either the fetal or uteroplacental vessels. The use of oral nifedipine to control blood pressure in preeclampsia does not affect the resistance indices in fetal or uteroplacental vessels as measured by the Doppler technique.