M. Bellotti

Fetal Plasma Leptin Concentrations: Relationship with Different Intrauterine Growth Patterns from 19 Weeks to Term

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6 ± 0.6 ng/mL;p < 0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p < 0.001) and fetal weight (p < 0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p < 0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p < 0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p < 0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.

Fetal echocardiography at the time of the nuchal translucency scan

The fetal heart is not studied routinely in the first trimester because of technical and time limitations. Our aim was to assess the feasibility of performing a fetal cardiac study in pregnancies referred for nuchal translucency (NT) screening, using high‐frequency linear transabdominal transducers with a specific ultrasound preset.

Mathematical modelling of the human foetal cardiovascular system based on Doppler ultrasound data

A lumped parameter model of the human foetal circulation primarily based on blood velocity data derived from the Doppler analysis was developed in this study. It consists of two major parts, the heart and the foetal vascular circulation. The heart model accounts for both ventricular and atrial contractility. The circulation was divided into 19 compliant vascular compartments in order to describe all of the clinically monitored sites. The model parameters refer to the final gestation period and were derived either from literature on foetal sheep circulation or from anatomical dimension monitoring of the human foetus. No control mechanism is incorporated into the model. The model was validated by comparing several index values of simulated velocity curves to those of the experimental Doppler waveforms. The mean and maximum percentual errors in the estimation of the experimental results by the model are 7.7% and 20.1%, respectively. Velocity and pressure tracings of the foetal circulation were investigated, as well as regional blood flow rate distribution.

Dilatation of the ductus venosus in human fetuses: ultrasonographic evidence and mathematical modeling.

Autonomic regulation of blood flow through the fetal ductus venosus has been suggested, but the existence of a sphincter at the ductal entrance in human fetuses has yet to be established. In this paper two cases of apparent ductus venosus dilatation in two growth-restricted human fetuses are reported. Prolonged ultrasonographic analysis (45 min) showed rapid and substantial changes (>80%) of ductal diameters. Pulsed Doppler analysis was used to investigate flow velocity in the ductus venosus and umbilical vein for both normal and dilated conditions. Dilated conditions caused manifest modifications of velocity tracings. Systolic peak velocity in the ductus did not change visibly, whereas velocity at the atrial contraction showed evident reduction; consequently, pulsatility indexes increased. Furthermore, the umbilical vein presented flow velocity pulsations. The mean blood flow rate through the ductus seemed to increase substantially (>70%) for high dilatation. To investigate these findings further, we performed simulations of ductal dilatation by means of a lumped-parameter mathematical model of the human fetal circulation. Model results agreed with clinical evidence and confirmed the relationship between ductal dilatation and the observed velocity alterations. Simulated systolic peak velocity slightly increased for small dilatation (<30%), whereas atrial velocity was reduced when the ductus dilated. Furthermore, the model indicated that umbilical venous pressure decreases for increasing dilatation, whereas no change occurs in the central venous pressure. The present results seem to indicate the presence of active dilatation of the ductus venosus in human fetuses.Autonomic regulation of blood flow through the fetal ductus venosus has been suggested, but the existence of a sphincter at the ductal entrance in human fetuses has yet to be established. In this paper two cases of apparent ductus venosus dilatation in two growth-restricted human fetuses are reported. Prolonged ultrasonographic analysis (45 min) showed rapid and substantial changes (>80%) of ductal diameters. Pulsed Doppler analysis was used to investigate flow velocity in the ductus venosus and umbilical vein for both normal and dilated conditions. Dilated conditions caused manifest modifications of velocity tracings. Systolic peak velocity in the ductus did not change visibly, whereas velocity at the atrial contraction showed evident reduction; consequently, pulsatility indexes increased. Furthermore, the umbilical vein presented flow velocity pulsations. The mean blood flow rate through the ductus seemed to increase substantially (>70%) for high dilatation. To investigate these findings further, we performed simulations of ductal dilatation by means of a lumped-parameter mathematical model of the human fetal circulation. Model results agreed with clinical evidence and confirmed the relationship between ductal dilatation and the observed velocity alterations. Simulated systolic peak velocity slightly increased for small dilatation (<30%), whereas atrial velocity was reduced when the ductus dilated. Furthermore, the model indicated that umbilical venous pressure decreases for increasing dilatation, whereas no change occurs in the central venous pressure. The present results seem to indicate the presence of active dilatation of the ductus venosus in human fetuses.

Computational analysis of the ductus venosus fluid dynamics based on Doppler measurements

The simplified Bernoulli equation is currently used to evaluate pressure gradients on the basis of Doppler velocity measurements when direct pressure data require highly invasive procedures. Recently, this method was applied to the ductus venosus (DV) in order to estimate the fetal central venous pressure. The complex geometry- and consequently hemodynamics-of this fetal region suggests caution in automatically converting Doppler velocity measurements to pressure data. To investigate the reliability of the Bernoulli equation for this practice, we simulated the hemodynamics of the branching between the umbilical vein (UV) and the DV on the basis of ultrasonographic data from a normal fetus, using a simplified parametric 3D numerical model of a bent tube with varying cross section (UV) and a smaller trumpet-shaped branch (DV). A finite element formulation has been adopted to solve the governing Navier-Stokes equations. The results show that the simplified Bernoulli equation, despite of its simplicity, provides a good estimation of the pressure drop between the UV and the DV outlet section (with an error of about 0.25 mmHg, equal to 15%, compared with the model results). Nevertheless, attention must be paid to the velocity measurement sites, as discussed in this paper. In turn, the error becomes notable (2.8 mmHg, i.e., 34%) for high velocity values, thus suggesting that the error in evaluating the pressure drop with the simplified Bernoulli equation during fetal inspiratory movements may be substantial.

Blood Flow Through the Ductus Venosus in Human Fetus: Calculation Using Doppler Velocimetry and Computational Findings

The present study was performed to assess a new method to calculate the blood flow rate through the ductus venosus (DV) in normal human fetuses using available echo-Doppler data. Color Doppler sonographic unit was used to study DV flow in 26 normal fetuses between 20 and 36 wk of gestation. Maximal velocity flow tracings and vessel diameters were obtained at the isthmic and the outlet portion of the DV. Time-averaged velocities in the DV were measured from the recorded tracings. The velocity distribution in the two investigated cross-sectional areas of the DV was evaluated by means of computational model simulations and the velocity shape coefficients h(in) and h(out), (i.e., the ratios between the maximal and mean spatial velocities) were calculated as a function of vessel geometry. These values allowed us to convert maximal Doppler velocities into mean spatial velocities for each fetus. Blood flow rate was evaluated both at the isthmus and at the outlet of the vessel by means of two formulae based on the ultrasonographic measures and the results of the computational model. The value of the DV blood flow rate was calculated as the average between the results provided by the two formulae. The velocity distributions both at the isthmus (h(in) = 0.677 +/- 0.040) and the outlet (h(out) = 0.374 +/- 0.072) of the ductus are skewed toward the inner wall. Ductus geometry, i.e., the isthmic/outlet diameter ratio, affects the shape of the velocity profiles in the vessel, particularly that at the outlet. The coefficients of variation for repeated measurements of the ductal diameters were 9.5 +/- 7.7% and 6.7 +/- 4.9% at the isthmus and the outlet, respectively. The two formulae gave values statistically identical for the time-average blood flow rate (36.3 +/- 22.1 vs. 39.4 +/- 24.0 mL/min; R = 0.946, p = NS). The mean percent difference between the results of the two formulae was 7.1%. Thus, in human fetuses, the use of the two formulae based on both Doppler data and computational model simulations makes it possible to calculate the ductal flow rate. When the difference between the calculations of the two formulae exceeds the 30% of their average value, it is convenient to adopt the flow rate value calculated at the isthmus instead of the average of the two measures. The measurements at the outlet of the ductus were more difficult to obtain, and the spatial velocity profile at the outlet depends more on the DV anatomy.

The correlation of biochemical monitoring versus umbilical flow velocity measurements of the human fetus

The pulsatility index of the fetal umbilical arteries was evaluated in 14 high-risk pregnant patients delivered by cesarean section between 30 and 35 weeks of gestation. Transabdominal cord sampling by ultrasonic guidance was performed on 10 of these patients. Umbilical arterial and venous blood was obtained in all patients from the doubly clamped cord at the time of cesarean section. The blood samples were analyzed for respiratory gases, acid-base balance, and lactate concentrations. A significant relationship was found between the pulsatility index and pH, PCO2, and lactate concentrations measured on umbilical venous blood sampled in utero. The pulsatility index also correlated with the same variables measured on venous and arterial blood sampled at cesarean section. Umbilical venous blood obtained transabdominally had a significantly higher oxygen content than blood obtained at cesarean section. No significant correlation was found between umbilical venous oxygen content obtained at transabdominal cord sampling and the pulsatility index. At a pulsatility index greater than 1.5, lactate concentrations in umbilical venous blood increased sharply. There would appear to be a curvilinear relationship between umbilical blood flow and these indices of fetal oxygenation, such that moderate increases in pulsatility index were not associated with a significant increase in fetal lactate concentrations.

Doppler velocimetry: critical analysis of umbilical, cerebral and aortic reference values

Cross-sectional reference standards of the umbilical flow velocity waveforms were investigated from 18 to 38 weeks of gestation on 482 normal pregnancies. A significant decrease in the pulsatility index (PI) and systolic/diastolic (SD) ratio was observed during gestation. This phenomenon was confirmed in a longitudinal study on 150 patients of the same population. The two slopes of cross-sectional and longitudinal data were not significantly different. A bimodal distribution of PI and S/D ratio was observed. Six per cent of data fell above the vast majority of cases. The dimension of the population studied allowed us to consider these findings not as outliers but as an interesting transient phenomenon of very low end-diastolic velocities which can occur in normal fetuses, without concomitant variations on the thoracic aorta and middle cerebral artery. Cross-sectional reference ranges were studied for these vessels on the same population from 26 to 38 weeks of gestation. A significant decrease in the PI of the middle cerebral artery was observed versus a significant increase in the PI of the thoracic aorta. These latter indices could be used to obtain indirect information on the normal redistribution of blood flow in the human fetus in the third trimester of gestation. However, the great variability observed should warn against the risks of a simplistic clinical use of these observations.

Peak velocity of the outflow tract of the aorta: Correlations with acid base status and oxygenation of the growth-retarded fetus

Objective To correlate the peak velocities of the aortic outflow tract of growth-retarded fetuses with fetal acid base status and oxygenation measured in utero. Methods Thirty-one growth-retarded fetuses with abnormal umbilical pulsatility index (PI) measurements underwent fetal blood sampling. Blood pH, carbon dioxide pressure (PCO2), oxygen pressure (PO2), oxygen safuration, lactate concentration, and hemoglobin concentration were measured. Using color Doppler equipment, we measured the peak velocities of the outflow tract of the aorta, pulmonary artery, and ductus arteriosus before fetal blood sampling. Results The peak velocities measured in the outflow tract of the aorta, pulmonary artery, and ductus were significantly lower in growth-retarded fetuses than in 140 normal fetuses of comparable weight. The correlation observed between pulmonic and aortic peak velocities was significant (r = 0.84), as was that between pulmonic and ductal peak velocities (r = 0.74). Growth-retarded fetuses with abnormal aortic peak velocities had significantly lower values of PO2, oxygen content and pH, and had higher lactate concentration and PCO2 than did growth-retarded fetuses with normal peak velocities. Estimated fetal weight and umbilical PI (mean ± standard deviation) were not significantly different in these two groups. Moreover, significant direct correlations were found between proximal aortic peak velocities and lactate concentrations (correlation coefficient 0.71, P < .0001) and O2 content (P < .02, r = 0.42). Conclusion For growth-retarded fetuses, Doppler peak velocity in these vessels is significantly lower than in normal fetuses of comparable weight. Aortic, pulmonic, and ductal peak velocity correlated significantly. Growth-retarded fetuses with abnormally low peak velocity in the outflow tract of the aorta have a higher risk of acidemia and hypoxia than those with normal velocities.

Role of umbilical doppler velocimetry in the biophysical assessment of the growth-retarded fetus : answers from neonatal morbidity and mortality

We compared umbilical Doppler velocimetry with biophysical parameters, obstetrical management, and neonatal morbidity. The study of 85 pregnancies was prospective and blind both to the obstetric and pediatric staff. Our results show that under the same biophysical diagnosis, ie, abnormal fetal growth, oligohydramnios, and nonreactive cardiotocographics, the prevalence of neonatal morbidity was significantly higher in fetuses with associated abnormal umbilical pulsatility index (PI) in utero. Newborns with abnormal PI were delivered earlier, mostly for fetal indication, and were smaller and more asymmetrical than newborns with a normal PI in utero. The analysis of morbidity for homogeneous classes of weight showed that in the group of newborns between 1500 and 2500 g, newborns with normal umbilical PI did show only metabolic disturbances and one respiratory distress syndrome. On the contrary, newborns of the same gestational age and of the same weight with abnormal PI had more severe morbid episodes. In the class of weight between 1500 and 1000 g not only the severity but also the prevalence of neonatal morbidity was significantly higher in newborns with an abnormal PI in utero. None of the newborns delivered below 1000 g had a normal umbilical PI. Five died in the early neonatal period. Three suffered from mild neuromotor sequelae. Practical consequences of these findings on fetal management are the scheduled frequency of biophysical examinations, which must be closer and on an inpatient basis whenever abnormal, and the interpretation of other abnormal biophysical parameters, which must be considered as more severe whenever associated with an abnormal umbilical velocimetry.