Endothelin-1 signalling controls early embryonic heart rate in vitro and in vivo.

AIM: Spontaneous activity of embryonic cardiomyocytes originates from sarcoplasmic reticulum (SR) Ca(2+) release during early cardiogenesis. However, the regulation of heart rate during embryonic development is still not clear. The aim of this study was to determine how endothelin-1 (ET-1) affects the heart rate of embryonic mice, as well as the pathway through which it exerts its effects. METHODS: The effects of ET-1 and ET-1 receptor inhibition on cardiac contraction were studied using confocal Ca(2+) imaging of isolated mouse embryonic ventricular cardiomyocytes and ultrasonographic examination of embryonic cardiac contractions in utero. In addition, the amount of ET-1 peptide and ET receptor a (ETa) and b (ETb) mRNA levels were measured during different stages of development of the cardiac muscle. RESULTS: High ET-1 concentration and expression of both ETa and ETb receptors was observed in early cardiac tissue. ET-1 was found to increase the frequency of spontaneous Ca(2+) oscillations in E10.5 embryonic cardiomyocytes in vitro. Non-specific inhibition of ET receptors with tezosentan caused arrhythmia and bradycardia in isolated embryonic cardiomyocytes and in whole embryonic hearts both in vitro (E10.5) and in utero (E12.5). ET-1-mediated stimulation of early heart rate was found to occur via ETb receptors and subsequent inositol trisphosphate receptor activation and increased SR Ca(2+) leak. CONCLUSION: Endothelin-1 is required to maintain a sufficient heart rate, as well as to prevent arrhythmia during early development of the mouse heart. This is achieved through ETb receptor, which stimulates Ca(2+) leak through IP3 receptors.

OS077. The chromosome 2q22 preeclampsia susceptibility locus reveals shared novel risk factors for CVD.

INTRODUCTION: We have previously localized a preeclampsia susceptibility locus on chromosome 2q22 in 34 Australian and New Zealand (AUS/NZL) families. Using an extended number of AUS/NZL families (n=74) we have now performed a comprehensive molecular genetics dissection of this locus. OBJECTIVES: Identify causal genetic risk factors for preeclampsia at the 2q22 risk locus. METHODS: To prioritize positional candidate genes for analysis we used a combination of bioinformatics, SNPing, whole-genome transcriptional profiling and proximity to the peak linkage signal. Prioritized genes were earmarked for exon-centric re-sequencing in 48 founder individuals from the 74 AUS/NZL families. All identified sequence variants were genotyped back in this extended familial cohort. Variants showing the strongest genetic association were genotyped in independent case-control cohorts from Australia (n=1095), Norway (n=3397) and Finland (n=1519), and in a large cohort of Mexican American families rich in quantitative cardiovascular disease (CVD) risk traits. RESULTS: We interrogated 1598 variants from 52 genes and identified four independent SNPs to be significantly associated with preeclampsia susceptibility in the 74 AUS/NZL families. These four SNPs reside in four novel preeclampsia candidate genes: LCT (rs2322659, p=0.002), LRP1B (rs35821928, p=0.0001), RND3 (rs115015150, p=0.002) and GCA (rs17783344, p=0.002). We could only replicate the LCT SNP association in the Australian case-control population (p=0.04, combined p=0.001). These four SNPs are however, significantly associated with several quantitative CVD risk traits such as oxidative stress indicators, inflammatory biomarkers and obesity risk factors. CONCLUSION: Previous independent studies have reported significant genetic associations with total cholesterol levels and obesity risk factors for variants within LCT and LRP1B, respectively. RND3 inhibits the biological activity of a downstream effector protein, ROCK, which is known to affect endothelial dysfunction, inflammation, oxidative stress and vascular re-modeling. Grancalcin (GCA) is known to impact the adhesive properties of fibronectin, a marker for endothelial vascular injury. To our knowledge, data from the current study present for the first time empirical evidence of possible shared genetic risk factors underlying both preeclampsia and other CVD-related traits.

Significance of retrograde diastolic uterine artery blood flow during regional anesthesia in instrumented pregnant sheep.

BACKGROUND: We studied the interactions between uterine and placental hemodynamics during maternal hypotension in chronically instrumented fetal sheep. In addition, we investigated maternal hemodynamic characteristics, fetoplacental hemodynamics and fetal acid-base status when a retrograde diastolic uterine artery blood flow pattern is present during maternal hypotension. METHODS: Invasive maternal and fetal hemodynamic parameters, uterine (Q(UtA)) and placental (Q(UA)) volume blood flows and acid-base values were examined in 24 chronically instrumented sheep at baseline and during epidural-induced maternal hypotension at 117-132 (term 145) days of gestation. Uterine artery blood flow velocity waveforms were obtained by Doppler ultrasonography. RESULTS: Maternal hypotension decreased Q(UtA) without affecting Q(UA). During hypotension, eight out of 24 sheep demonstrated a retrograde diastolic blood flow velocity waveform pattern in the uterine artery. Maternal systolic, diastolic and mean arterial blood pressures were significantly lower in the retrograde group than in the antegrade group. No statistically significant differences in Q(UtA), Q(UA) and fetal blood gas values were detected between the two groups during hypotension. CONCLUSIONS: An acute decrease in uterine artery volume blood flow during maternal hypotension is not compensated by increased placental volume blood flow. A retrograde diastolic blood flow pattern in the uterine artery is related to lower maternal arterial pressures, especially during diastole. A uterine artery retrograde diastolic blood flow pattern does not have any additional detrimental short-term effects on fetal acid-base status.

Human fetal cardiovascular profile score and neonatal outcome in intrauterine growth restriction.

OBJECTIVE: To determine whether low cardiovascular profile (CVP) score has prognostic value for predicting neonatal mortality and severe morbidity in human fetuses with growth restriction. METHODS: Seventy-five consecutive growth-restricted fetuses with Doppler examination of cardiovascular hemodynamics within a week prior to delivery comprised the study population. Hydrops, heart size, cardiac function and venous and arterial hemodynamics were evaluated for CVP score. The primary outcome measures were neonatal mortality and cerebral palsy. RESULTS: During the neonatal period, six of 75 neonates died and two had cerebral palsy (Group 1, n = 8). Compared with the fetuses discharged home from hospital (Group 2, n = 67), those in Group 1 were delivered at an earlier gestational age (28 (range, 24-35) weeks vs. 35 (range, 26-40) weeks, P < 0.01) and had lower CVP scores (4 (range, 2-6) vs. 9 (range, 5-10), P < 0.0001). All CVP subscale scores were lower (P < 0.01) in Group 1 than in Group 2 fetuses. Gestational age-adjusted hazard ratios (95% CIs) for adverse neonatal outcome were highest for cardiomegaly (13.9 (1.7-114.3), P = 0.014), monophasic atrioventricular filling pattern or holosystolic tricuspid regurgitation (9.5 (2.3-38.4), P = 0.002) and atrial pulsations in the umbilical vein 7.7 (1.4-41.2), P = 0.017). CONCLUSIONS: Growth-restricted fetuses with adverse neonatal outcome have lower CVP scores than do fetuses with favorable neonatal outcome. The strongest predictors for adverse neonatal outcome in the CVP score were cardiomegaly, abnormal cardiac function with monophasic atrioventricular filling or holosystolic tricuspid regurgitation and increased systemic venous pressure. These assessments have independent prognostic power for adverse neonatal outcome even after adjustment for gestational age.

Divergent effects of ephedrine and phenylephrine on cardiovascular hemodynamics of near-term fetal sheep exposed to hypoxemia and maternal hypotension.

BACKGROUND: We hypothesized that the administration of ephedrine and phenylephrine for maternal hypotension modifies cardiovascular hemodynamics in near-term sheep fetuses. METHODS: At 115-136 days of gestation, chronically instrumented, anesthetized ewes with either normal placental function or increased placental vascular resistance after placental embolization were randomized to receive boluses of ephedrine (n = 12) or phenylephrine (n = 12) for epidural-induced hypotension after a short period of hypoxemia. Fetal cardiovascular hemodynamics were assessed by Doppler ultrasonography at baseline, during hypotension and after vasopressor treatment. RESULTS: During hypotension, fetal PO(2) decreased and proximal branch pulmonary arterial and pulmonary venous vascular impedances increased. Additionally, in the embolized fetuses, the time-velocity integral ratio between the antegrade and retrograde blood flow components of the aortic isthmus decreased. These parameters were restored to baseline conditions by ephedrine but not by phenylephrine. With phenylephrine, weight-indexed left ventricular cardiac output and ejection force decreased in the non-embolized fetuses, and the proportion of isovolumetric contraction time of the total cardiac cycle was elevated in the embolized fetuses. CONCLUSIONS: After exposure to hypoxemia and maternal hypotension, ephedrine restored all fetal cardiovascular hemodynamic parameters to baseline. Phenylephrine did not reverse fetal pulmonary vasoconstriction or the relative decrease in the net forward flow through the aortic isthmus observed in fetuses with increased placental vascular resistance. Moreover, fetal left ventricular function was impaired during phenylephrine administration.

Experimental validation of uterine artery volume blood flow measurement by Doppler ultrasonography in pregnant sheep.

OBJECTIVE: To test the hypothesis that Doppler-derived (calculated) uterine artery volume blood flow (cQ(UtA)) reflects accurately volume blood flow measured directly (mQ(UtA)) in an experimental setting. METHODS: Five pregnant sheep were instrumented at 122-130 days of gestation under general anesthesia. After a 4-day recovery period, maternal hemodynamics were varied by administering to the sheep under general anesthesia noradrenaline, beta-blocker, low oxygen gas mixture, epidural bupivacaine and ephedrine, consecutively. The central venous pressure was obtained with the help of a thermodilution catheter. The mean arterial pressure and acid-base status were monitored using a 16-gauge polyurethane catheter inserted into the descending aorta via a femoral artery. A 6-mm transit-time ultrasonic perivascular flow probe was used to measure the mQ(UtA). Doppler ultrasonography of the uterine artery was performed and volume blood flow was obtained simultaneously by the transit-time ultrasonic perivascular flow probe during each phase of the experiment. RESULTS: A total of 31 observations were made. The mQ(UtA) varied between 90 and 800 (mean +/- SD, 419 +/- 206) mL/min during the experiments. The corresponding values for the cQ(UtA) were 110 and 900 (mean +/- SD, 459 +/- 211) mL/min. There was a significant correlation (R = 0.76; P < 0.0001) between mQ(UtA) and cQ(UtA). The mQ(UtA) correlated positively with Doppler-derived uterine artery absolute velocities, i.e. peak systolic (R = 0.50; P = 0.004), end-diastolic (R = 0.53; P = 0.002) and time-averaged maximum (R = 0.69; P < 0.0001) and time-averaged intensity weighted mean (R = 0.75; P < 0.0001) velocities. CONCLUSION: cQ(UtA) correlates well with volume blood flow measured directly. Doppler-derived uterine artery absolute blood flow velocities reflect uteroplacental volume blood flow in pregnant sheep. Published by John Wiley & Sons, Ltd.

Cardiovascular hemodynamics and umbilical artery N-terminal peptide of proB-type natriuretic peptide in human fetuses with growth restriction.

OBJECTIVE: To test our hypothesis that human fetal N-terminal peptide of proB-type natriuretic peptide (NT-proBNP) secretion is increased in proportion to the severity of fetal cardiovascular compromise in intrauterine growth restriction. METHODS: This prospective cross-sectional study consisted of 42 growth-restricted fetuses who underwent Doppler ultrasonographic examination of cardiovascular hemodynamics within 7 days before delivery. Group 1 fetuses (n = 13) had normal umbilical artery (UA) velocimetry. Group 2 fetuses (n = 15) had abnormal UA and normal ductus venosus (DV) velocimetry. In Group 3 fetuses (n = 14), both UA and DV velocimetries were abnormal. At delivery, an UA blood sample was obtained for assessment of NT-proBNP. Normal values for UA NT-proBNP were determined in 49 neonates (control group) with uncomplicated pregnancy and delivery. RESULTS: Group 3 fetuses demonstrated greater (P < 0.05) UA and descending aorta pulsatility indices (PIs) and greater DV, left hepatic vein (LHV) and inferior vena cava PIs for veins (PIVs) than fetuses in Groups 1 and 2. Weight-indexed cardiac outputs and ventricular ejection forces were similar among the groups. Group 3 fetuses had higher (P < 0.05) UA NT-proBNP concentration than fetuses in Groups 1 and 2. In the control group, the 95(th) percentile value of UA NT-proBNP was 518 pmol/L. In Group 3, 13/14 neonates demonstrated abnormal UA NT-proBNP levels. The corresponding incidences were 4/13 and 7/15 in Groups 1 and 2. Significant positive correlations were found between UA, DV and LHV PIVs and UA NT-proBNP concentrations. CONCLUSION: In human fetal growth restriction, increased cardiac afterload and pulsatility in DV blood velocity waveform pattern are associated with elevated UA NT-proBNP concentrations.

A comparison of intrapartum automated fetal electrocardiography and conventional cardiotocography--a randomised controlled study.

OBJECTIVE: To examine whether intrapartum monitoring by means of automatic ST analysis (STAN) of fetal electrocardiography could reduce the rate of neonatal acidemia and the rate of operative intervention during labour, compared with monitoring by means of cardiotocography (CTG). DESIGN: Randomised controlled trial. SETTING: Labour ward in tertiary-level university hospital. SAMPLE: A total of 1483 women in active labour with singleton term fetus in cephalic presentation. METHODS: Women were randomly assigned to be monitored either by STAN or by CTG. Fetal blood sampling (FBS) was optional in both groups. MAIN OUTCOME MEASURES: Neonatal acidemia (umbilical artery pH <7.10), neonatal metabolic acidosis (umbilical artery pH <7.05 and base excess <-12 mmol/l) and operative interventions: caesarean section rate, vacuum outlet (VO) rate and FBS rate. RESULTS: There were no statistically significant differences between the STAN group and CTG group in the incidence of neonatal acidemia (5.8 versus 4.7%) or metabolic acidosis (1.7 versus 0.7%). The caesarean section rate (6.4 versus 4.7%) and the VO rate (9.5 versus 10.7%) were also similar in the STAN and CTG groups. The incidence of FBS was lower (P < 0.001) in the STAN group (7.0%) than in the CTG group (15.6%). CONCLUSIONS: Intrapartum fetal monitoring by means of automatic STAN did not improve the neonatal outcome or decrease the caesarean section rate. However, the need for FBS during labour was lower in the STAN group.

Ephedrine and phenylephrine for the treatment of maternal hypotension in a chronic sheep model of increased placental vascular resistance.

BACKGROUND: We hypothesized that ephedrine and phenylephrine are equal with respect to uterine and placental haemodynamics and fetal acid-base status after exposure to maternal hypoxaemia and hypotension in a chronic sheep model of increased placental vascular resistance (R(UA)). METHODS: At 114-135 days gestation, chronically instrumented fetal sheep underwent placental embolization leading to increased R(UA). Twenty-four hours after embolization, the ewes were anaesthetized and randomized to receive boluses of ephedrine (n=7) or phenylephrine (n=6) for epidural-induced hypotension after maternal hypoxaemia. Uterine (Q(UtA)) and placental (Q(UA)) volume blood flows and uterine vascular resistance (R(UtA)) and R(UA) were recorded. Uterine (PI(UtA)) and umbilical artery (PI(UA)) pulsatility indices were obtained by Doppler ultrasonography. Fetal arterial blood samples were analysed for acid-base values and lactate concentrations. RESULTS: During hypotension, Q(UtA), fetal pH, BE, and Po(2) decreased whereas R(UtA), PI(UtA), R(UA), and fetal lactate concentration increased. With ephedrine, Q(UtA), R(UtA), PI(UtA), R(UA), and fetal Po(2) returned to baseline. Fetal pH, BE, and lactate concentration did not change from hypotensive values. With phenylephrine, Q(UtA) remained lower (P=0.007) and R(UtA) (P=0.007), PI(UtA) (P=0.013), and R(UA) (P=0.050) higher than at baseline. Fetal Po(2) returned to baseline and fetal pH and BE did not change from hypotensive values. However, fetal lactate concentration increased further (mean difference 1.49, 95% confidence interval 0.72-2.26 mmol litre(-1); P=0.004). CONCLUSIONS: In a chronic sheep model of increased placental vascular resistance, compared with ephedrine administration, phenylephrine administration was associated with impaired uterine and placental haemodynamics and increased fetal lactate concentrations.

Low-dose aspirin does not improve ovarian responsiveness or pregnancy rate in IVF and ICSI patients: a randomized, placebo-controlled double-blind study.

BACKGROUND: Poor ovarian and endometrial responses to gonadotrophin stimulation in assisted reproduction techniques lead to decreased pregnancy rates. The aim of the present study was to test the hypothesis that low-dose aspirin started prior to controlled ovarian stimulation improves ovarian responsiveness, pregnancy rate (PR) and pregnancy outcome. METHODS: A total of 374 women who were to undergo IVF/ICSI were randomized to receive 100 mg of aspirin (n=186) or placebo (n=188) daily. Treatment was started on the first day of controlled ovarian stimulation. It was continued until menstruation or a negative pregnancy test. Pregnant women continued the medication until delivery. The main outcome measures were the number of oocytes, number and quality of embryos, the clinical PR and pregnancy outcome. RESULTS: The mean (+/-SD) number of oocytes (12.0+/-7.0 versus 12.7+/-7.2), the total mean number of embryos (5.82+/-4.35 versus 5.99+/-4.66), the mean number of top quality embryos (0.99+/-1.39 versus 1.18+/-1.51) and the number of embryos transferred (1.64+/-0.64 versus 1.63+/-0.71) did not differ in the aspirin and placebo groups. Between the aspirin and placebo group, there was no statistically significant difference in clinical PR per embryo transfer (25.3%, n=44 out of 174 versus 27.4%, n=48 out of 175) or clinical PR per cycle initiated (23.7% versus 25.5%). Birth rate per embryo transfer did not differ significantly between the aspirin (18.4%) and placebo (21.1%) groups. The incidence of poor responders [12 (6.5%) versus 13 (6.9%)] was similar in both groups. CONCLUSIONS: The present results indicate that low-dose aspirin treatment does not have any beneficial effect on ovarian responsiveness, PR and pregnancy outcome in unselected women undergoing IVF/ICSI.

Human fetal cardiac function during the first trimester of pregnancy.

OBJECTIVE: To investigate first trimester human fetal cardiac function in relation to cardiac volume blood flow, and peripheral arterial and venous blood flow patterns. METHODS: Transvaginal Doppler ultrasonography was performed in 16 uncomplicated pregnancies at 6+, 7+, 8+, 9+, and 10+ gestational weeks. The shape of the inflow waveform and the presence of atrioventricular valve regurgitation (AVVR) were noted. The outflow mean velocity (Vmean) was calculated. The proportions of the isovolumetric relaxation (IRT%) and contraction times (ICT%) of the cardiac cycle were defined. Ductus venosus and umbilical artery pulsatility indices (PI) were obtained. RESULTS: Every inflow waveform was monophasic before 9+ weeks. At 9+ weeks 11 of 16 and at 10+ weeks all waveforms were biphasic. At 7+ and 8+ weeks AVVR was documented in one case. At 9+ and 10+ weeks AVVR was present in four and seven fetuses, respectively. Mean (SD) outflow Vmean increased between 6+ and 8+ weeks from 3.6 (1.5) to 8.4 (3.0) cm/s (p < 0.05). IRT% decreased significantly from 6+ to 7+ weeks (39.8 (2.6) to 19.2 (6.2), p < 0.001). ICT% decreased between 8+ and 9+ weeks from 13.2 (4.0) to 8.5 (2.5) (p < 0.05). Ductus venosus PIs were unchanged. Umbilical artery Vmean increased between 7+ and 10+ weeks from 1.59 (0.51) to 5.06 (1.06) cm/s (p < 0.001) and PIs remained unchanged. CONCLUSIONS: The first trimester of pregnancy is characterised by significant improvements in cardiac diastolic and systolic function with a concomitant increase in cardiac volume blood flow. At 10+ weeks AVVR is a common finding. Placental volume blood flow increases significantly with no change in the placental vascular impedance.

Effects of ephedrine and phenylephrine on uterine and placental circulations and fetal outcome following fetal hypoxaemia and epidural-induced hypotension in a sheep model.

BACKGROUND: Recent studies support the use of alpha-agonists during regional anaesthesia in uncomplicated term pregnancies. We hypothesized that ephedrine and phenylephrine, administered for maternal hypotension following fetal hypoxaemia, are equal in respect of fetal outcome. METHODS: At 117-132 days gestation, chronically instrumented, anaesthetized and mechanically ventilated ewes were randomized to receive boluses of ephedrine (n=9) or phenylephrine (n=8) for maternal epidural-induced hypotension after a period of fetal hypoxaemia. Uterine (QUtA) and placental (QUA) volume blood flows were measured with perivascular transit-time ultrasonic flow probes, and uterine (RUtA) and placental (RUA) vascular resistances were computed from volume blood flows and maternal and fetal mean arterial pressures. Uterine (PIUtA) and umbilical artery (PIUA) pulsatility indices were obtained by Doppler ultrasonography. RESULTS: Ephedrine increased QUtA and decreased RUtA and PIUtA from a hypotensive to baseline level and had no significant effect on umbilical circulation. With phenylephrine, QUtA remained lower (P=0.011) and RUtA higher (P=0.043) than at baseline, although PIUtA decreased to baseline level. PIUA increased from baseline with phenylephrine (P=0.007), whereas QUA decreased (P=0.050). Maternal volume expansion with hydroxyethyl starch decreased RUtA significantly irrespective of the vasopressor used. There were no significant differences in fetal blood gas values or lactate concentrations between the ephedrine and phenylephrine groups. CONCLUSIONS: Despite the more favourable effects on uterine and placental circulations of ephedrine over phenylephrine, no significant differences in fetal acid-base status or lactate concentrations were observed.

Uteroplacental hemodynamics during early human pregnancy: a longitudinal study.

BACKGROUND: To determine normal physiologic changes in the uteroplacental hemodynamics during early placental development in the first trimester of pregnancy. METHODS: Sixteen normal singleton pregnancies were included in this longitudinal study. Transvaginal Doppler ultrasonographic examinations of uterine, arcuate, radial and spiral arteries were performed at the 5th, 7th, 8th and 10th completed gestational weeks. Peak systolic velocity (PSV), time-averaged maximum velocity (TAMXV) and the pulsatility index (PI) were measured. RESULTS: Uterine artery PSV, TAMXV and PI remained unchanged from the 5th to the 8th week of gestation. From the 8th to the 10th week, PSV (p = 0.02) and TAMXV (p = 0.005) increased and PI decreased (p = 0.006). Changes in the arcuate arteries were similar to those in uterine arteries. No significant changes in PSV, TAMXV or PI of the radial artery were noticed. Spiral artery PSV (p = 0.02) and TAMXV (p = 0.02) increased from the 5th to the 7th week. Thereafter they remained unchanged. Spiral artery PI decreased from the 5th to the 10th week, (p = 0.004). Throughout the study period, the PSV, TAMXV and PI values were significantly higher in the uterine artery than in the arcuate artery, and in the arcuate artery compared with the radial artery. At the 5th gestational week, no differences in PSV and TAMXV were found between radial and spiral arteries. From the 7th gestational week onwards, PSV and TAMXV were significantly lower in the radial artery than in the spiral artery. However, the PI values in the radial artery were significantly higher compared with those in the spiral artery during the whole study period. CONCLUSIONS: Spiral artery impedance decreases and blood flow velocities increase as early as between the 5th and the 7th weeks of gestation. During that period, the uterine and arcuate artery hemodynamics remain unchanged. In the uterine and arcuate arteries, decreases in impedance and increases in absolute velocities are detected after the 8th week of gestation. This delay between the changes in the spiral and uterine arteries may represent the magnitude of the increase of placental volume and spiral arterial involvement which is needed to affect uterine hemodynamics.

First trimester uterine, placental and yolk sac haemodynamics in pre-eclampsia and preterm labour.

BACKGROUND: We hypothesized that impaired trophoblast invasion leads to umbilicoplacental blood flow disturbances that could be detected by Doppler ultrasonography during the first trimester of the pregnancy. METHODS: After successful fresh IVF or ICSI programme, 41 of 47 enrolled subjects were followed up every 1-2 weeks between weeks 6 and 11 of gestation. Ten patients who later developed pre-eclampsia and/or preterm labour formed the study group and the control group consisted of 31 uncomplicated IVF/ICSI pregnancies. Doppler parameters of uterine, spiral, intraplacental, chorionic, umbilical and yolk sac haemodynamics were assessed. RESULTS: At the week 8, the study group demonstrated higher (P < 0.05) maternal intraplacental resistance indices (RI) than the control group. A week later, yolk sac artery RI and umbilical artery mean velocity (V(mean)) in the study group were lower (P < 0.05) compared to the control group. In late first trimester, increased (P < 0.01) velocities and RI were observed in chorionic arteries of the study group. During early pregnancy, no difference in uterine and spiral artery haemodynamics and in umbilical artery pulsatility index (PI) values was observed between the groups. CONCLUSIONS: Uterine and spiral artery RI and umbilical artery PI are unable to detect placental vascular disturbances during early pregnancy. Elevated intraplacental RI indicates increased maternal intraplacental impedance as early as week 8 of gestation. Decreased yolk sac artery RI and umbilical artery V(mean) in the study group at week 9 of gestation were speculated to indicate hampered transition of blood supply from yolk sac to umbilical circulation, underlining the emphasized role of yolk sac function for the maintenance of pregnancy.

Retrograde aortic isthmus net blood flow and human fetal cardiac function in placental insufficiency.

OBJECTIVE: Retrograde aortic isthmus (AoI) net blood flow has been associated with diminished oxygen delivery to cerebral circulation. This study was designed to characterize the cardiac function in human fetuses with retrograde AoI net blood flow in pregnancies complicated by placental insufficiency. METHODS: The control group comprised 43 fetuses in uncomplicated pregnancies. Study groups consisted of fetuses with placental insufficiency, and either antegrade (Group 1; n = 18) or retrograde (Group 2; n = 11) AoI net blood flow. Volume blood flows (Q) of left (LVCO) and right (RVCO) ventricles, ductus arteriosus (Q(DA)), pulmonary arterial bed (Q(P)) and foramen ovale (Q(FO)) were calculated and their proportions (%) of combined cardiac output (CCO) were determined. Ventricular ejection forces were calculated. Blood velocity waveforms of the mitral (MV) and tricuspid (TV) valves were obtained. The proportion of left ventricular isovolumetric relaxation time (IRT%) of the cardiac cycle, and index of myocardial performance (IMP) were calculated. RESULTS: In Group 1, Q(DA)% was increased (P < 0.05) and Q(P)% decreased (P < 0.05) compared with the control group, and Q(FO)% was greater (P < 0.01) compared with the control group and Group 2. In Group 2, the distribution of CCO did not differ from that of the control group. Ventricular ejection forces were similar among the groups. In Group 2, the MV early filling/atrial contraction time-velocity integral ratio was greater (P < 0.05) compared with those of the control group and Group 1. In Groups 1 and 2, IRT% and IMP were increased (P < 0.001) compared with the control group. CONCLUSIONS: In placental insufficiency, fetuses with antegrade AoI net blood flow show a shift in RVCO from the pulmonary to the systemic circulation, and Q(FO) makes up the majority of LVCO. Fetuses with retrograde AoI net blood flow fail to demonstrate these changes, suggesting a relative drop in the oxygen content of the blood entering the left ventricle.

Retrograde net blood flow in the aortic isthmus in relation to human fetal arterial and venous circulations.

OBJECTIVES: To characterize changes in the human fetal arterial and venous circulations associated with retrograde aortic isthmus net blood flow. METHODS: Study groups consisted of fetuses with placental insufficiency and/or fetal growth restriction and either antegrade (Group 1; n = 18) or retrograde (Group 2; n = 11) net blood flow in the aortic isthmus. The control group comprised 31 fetuses in uncomplicated pregnancies. Pulsatility indices of the umbilical, middle cerebral and proximal pulmonary arteries and the descending aorta, and pulsatility indices for veins of the ductus venosus and inferior vena cava were calculated. Right and left ventricular fractional shortenings were ascertained. The coronary artery blood flow was visualized and the presence of tricuspid regurgitation was noted. RESULTS: In the study groups, the umbilical artery and descending aorta pulsatility indices were significantly higher (P < 0.05), and those of the middle cerebral artery lower (P < 0.001), than in the control group, with no difference between the two study groups. The proximal pulmonary artery pulsatility index was significantly higher in Group 2 (P < 0.001) than in Group 1 and the control group. In Group 2, the right ventricular fractional shortening was significantly lower (P < 0.01) than in Group 1. Coronary artery blood flow was visualized significantly more often (P < 0.03) and tricuspid regurgitation was present more frequently (P < 0.003) in Group 2 than in Group 1. In Group 2, the ductus venosus pulsatility index for veins was significantly higher than in Group 1 (P < 0.01) and the control group (P < 0.01), with no difference in the inferior vena cava pulsatility index for veins. CONCLUSIONS: Fetuses with retrograde aortic isthmus net blood flow demonstrate a rise in right ventricular afterload and increased pulsatility in ductus venosus blood velocity waveforms.

Umbilical artery N-terminal peptide of proatrial natriuretic peptide in hypertensive pregnancies and fetal acidemia during labor.

OBJECTIVE: To assess the activity of the human fetal atrial natriuretic peptide system in hypertensive pregnancies with and without signs of increased fetal systemic venous pressure and in pregnancies complicated by fetal acidemia during labor. METHODS: Umbilical artery plasma N-terminal peptide of proatrial natriuretic peptide concentrations were measured in neonates by radioimmunoassay. The control group consisted of 50 neonates with uncomplicated gestation and labor. In group 1, there were 22 newborns of hypertensive pregnancies. Doppler ultrasonography showed abnormal umbilical artery blood velocity waveform in five cases and normal nonpulsatile umbilical vein blood velocity profile in every case. Group 2 consisted of five newborns of pregnancies complicated by maternal hypertensive disorder. Atrial pulsations in the umbilical vein and retrograde diastolic blood velocity pattern in the umbilical artery were detected in every case. Group 3 was composed of 27 newborns of uncomplicated pregnancies with fetal acidemia (pH 7.10 or less) during labor. RESULTS: In groups 1-3, N-terminal peptide of proatrial natriuretic peptide concentrations were higher (P <.001) than in the control group. In group 1, neonates with abnormal umbilical artery blood velocity pattern had higher N-terminal peptide of proatrial natriuretic peptide concentrations than neonates with normal umbilical artery Doppler findings (P <.006). N-terminal peptide of proatrial natriuretic peptide concentrations were higher in group 2 (P <.002) than in groups 1 and 3. CONCLUSIONS Maternal hypertensive disorder and fetal acidemia during labor stimulate fetal atrial natriuretic peptide production, which was greatest in fetuses with severe placental insufficiency and signs of congestive heart failure.

Effects of bleeding on uteroplacental, umbilicoplacental and yolk-sac hemodynamics in early pregnancy.

OBJECTIVE: To determine the influence of vaginal bleeding with or without a persisting subchorionic hematoma on uteroplacental, umbilicoplacental and yolk-sac hemodynamics in early pregnancy. DESIGN: Twenty-six consecutive patients with vaginal bleeding entered this longitudinal study 1-3 days after the beginning of vaginal bleeding and were re-examined every 1-2 weeks. In three cases vaginal bleeding occurred at the 5th completed gestational week, in 13 at the 7th week, in nine at the 8th week and in one case at the 10th week. A subchorionic hematoma was identified in one case at the 5th week, in nine cases at the 7th week, in nine cases at the 8th week, and in seven cases at the 10th week. Four pregnancies ended in miscarriage. Blood velocity waveforms of uterine, arcuate, radial, spiral, umbilical, chorionic and yolk-sac arteries were obtained by transvaginal pulsed Doppler ultrasound and peak systolic velocities, time-averaged maximum velocities and pulsatility indices were calculated. The results were compared with our earlier observations in normal pregnancy obtained with a similar study protocol. RESULTS: At the 7th week, radial artery pulsatility-index values (mean (SD)) were higher in pregnancies with vaginal bleeding (1.84 (0.59); P = 0.04) and in pregnancies with a subchorionic hematoma (1.96 (0.63); P = 0.03) than in normal pregnancies (1.40 (0.46)). The pulsatility-index values of uterine, arcuate, spiral, umbilical and chorionic arteries did not differ between the groups. Vaginal bleeding with or without a subchorionic hematoma at the 8th week did not affect any of the measured parameters. Persistence of the subchorionic hematoma until the 10th week did not affect uterine, arcuate, radial, spiral, umbilical or chorionic artery hemodynamics. Yolk-sac hemodynamic parameters did not differ between the groups. CONCLUSIONS: Vaginal bleeding with or without a subchorionic hematoma is associated with increased radial artery impedance at the 7th week of pregnancy. Persistence of the subchorionic hematoma does not affect utero- and umbilicoplacental circulation.

Association of severe placental insufficiency and systemic venous pressure rise in the fetus with increased neonatal cardiac troponin T levels.

OBJECTIVE: The aim of this study was to test the hypothesis that severe placental insufficiency and a rise in fetal systemic venous pressure are associated with fetal myocardial cell damage, which in turn leads to increased neonatal troponin T levels. STUDY DESIGN: Sixty-six neonates born after uncomplicated pregnancy and delivery were included in the control group. Study groups 1 and 2 consisted of 32 and 5 neonates, respectively, born to women with hypertensive disorder. In study group 1 the fetal intra-abdominal portion of the umbilical vein showed normal nonpulsatile blood flow pattern in every case. In study group 2 all the fetuses had atrial pulsations in the intraabdominal umbilical vein. After delivery blood samples were collected from the umbilical arteries, and cardiac troponin T concentrations were measured with commercially available enzyme-linked immunosorbent assay kits. A clinically significant troponin T level was set at >/=0.10 ng/mL. RESULTS: In study group 1 the maternal main uterine arterial blood flow pattern was normal in 30 cases and abnormal in 2 cases. Umbilical artery blood velocity waveforms were normal in 26 fetuses, 4 fetuses had a decreased diastolic blood flow, 1 fetus had an absent diastolic blood flow pattern, and 1 fetus had a retrograde diastolic blood flow pattern. In study group 2 maternal uterine arterial Doppler findings were abnormal in every case, and all the fetuses had retrograde diastolic blood flow pattern in the umbilical artery. Neonatal troponin T levels were <0.10 ng/mL in the control group (0-0.14 ng/mL) and in study group 1 (0-0.16 ng/mL), except for 1 case in each group. Every neonate in study group 2 had a troponin T level >0.10 ng/mL, with the range from 0.11 to 0.35 ng/mL. In study group 2 troponin T concentrations were significantly higher (P <.0001) than in either the control group or study group 1. CONCLUSION: Neonatal troponin T levels are not clinically significantly increased in normal pregnancies and in pregnancies complicated by maternal hypertensive disorder but with normal fetal umbilical venous return. Neonatal troponin T concentrations are significantly increased in the presence of abnormal umbilical venous return, which indicates myocardial cell damage.