Doppler Interrogation of the Umbilical Venous Flow Enrico Ferrazzi, Serena Rigano

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Introduction

The first reports about measurements of fetal umbilical venous blood flow in human fetuses go back to the early 1980s. Eik-Nes et al. in 1980 [1], Gill et al.

in 1981 [2], and Eik-Nes et al. in 1982 [3] reported measurements obtained on the ªintrahepaticº umbilical vein. It was not always certain whether these were sampled before the portal sinus, i.e., the origin of the portal veins. This pioneering era came to an end when Erskine and Ritchie [4] and Giles et al. [5]

came to the conclusion that ªThe results obtained are in keeping with previous studies but indicate that, although the method is relatively simple, determination of absolute blood flow in these vessels has little clinical potential because of inherent measurement inaccuracies.º Fortunately, over more than a decade, these statements on quantitative ªmeasurement inac- curaciesº and on ªpoor clinical potentialº in the diag- nosis of fetal growth restriction were challenged, among others by Gerson et al. [6], Reed et al. [7], Sutton et al. [8], Schmidt et al. [9], and Challis et al.

[10].

In the past 20 years the potential role of the measurement of flow, in the umbilical vein, ductus venosus, and cardiac outflow tract, was perceived as a possible direct insight into the core of pathophysiology, not just how it looks, but how it works; however, the real limitation was set by expensive research ultrasound machines, and by the expertise of research sonologists, until high-technology digital instruments became the standard of quality in commercial ultrasound units.

Fetal Flow Volume Measurements in the Era of Digital Computing and Imaging

Sources of Inaccuracies

Even if all other hemodynamic variables were considered negligible, which is not the case, an error of 15% in diameter measurement could determine a ma-

jor error in the calculation of flow itself since flow is determined according to the following equation:

UV flow ml=min

cross-sectional area p radius² mm²

mean velocity mm=s 60;

where linear measurements are squared and so is the error. Similar but more complex adjustment should be made for the error in the angle of interrogation of the Doppler beam, which at its best could be cor- rected on one plane, that of the plane of the image itself, but not within the thickness of the sonographic ªsliceº of the vessel. The third source of error is determined by the attempt to calculate the true mean velocity. Most sonographic software is designed to extract the mean velocity out of the instantaneous Doppler shift analysis, as an intensity-weighted mean velocity; however, when interrogated peak velocities are relatively slow (14±18 cm/s from 20 to 38 weeks of gestation) the amount of blood flow ªcutº by high- pass filters becomes relevant, and in addition to this, each software operates on analog-to-digital conver- sion of the Doppler shift and on the signal-to-noise ratio which is largely dependent on the gain and on the software itself. The complex issue of precise assessment of mean velocity is also biased by the difference between two-dimensional imaging and three-dimensional reality. The ideal flow model is a perfect parabolic flow evenly distributed in the vessel in which the mean velocity is half that of the peak velocity (mean velocity = peak velocity ´ 0.5) measured in the cross-sectional area. Again we must un- derline that Doppler sample volumes are closer to a bi-dimensional sample volume more than to a whole cross-sectional sample volume. Peak velocity is a simple measurement, and that measured in a two-dimensional and a three-dimensional model are equal. The mean instantaneous velocity could be calculated by a simple coefficient which takes into account the shape of the flow in the cross-sectional area. Unfortunately, the conditions of perfect parabolic flow are seldom met in the umbilical vein. According to Pennati and co-workers [11] one should take into account the fact

Doppler Interrogation of the Umbilical Venous Flow

Enrico Ferrazzi, Serena Rigano

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that close to the placenta the flow profile is closer to a flat profile in which the mean velocity and peak velocity differs by a coefficient of 0.74, whereas all along the free loops this coefficient is 0.61. This is higher than 0.5 and normative data derived from the formula reported above underestimate true flow by 18%.

Source of Accuracy

Imaging quality, color imaging quality, and pulsed Doppler velocimetry quality of today's technology are an obvious challenge to these limitations (Fig. 30.1).

In 1999 [12] we checked the intra- and inter-observer coefficients of variation of the umbilical vein diameter, mean velocity, and absolute flow. The diameter was calculated as the mean of three measurements on a magnified section of the cord. The brightest spot at low amplification was assumed as the best marker of true diameter. The brightest ultrasound echoes are in fact those reflected back by orthogonal

surfaces, which can be the case only when the ultrasound plane intersects the vessel at its true maximum diameter (Fig. 30.1). The ultrasound probe was tilted b y 908 and the Doppler beam was spotted on the same section of the vessel where the diameter was measured. We considered that it was more reproduci- ble, simpler, and probably more accurate, to assume for the given viscosity of blood, the diameter of the vessel and its length that an ideal parabolic flow truly occurs in those tracts of the umbilical vein where the lumen is linear for at least an approximate length of three times its diameter. The intra-observer coefficients of variation for the vein diameter, mean velocity, and absolute umbilical venous blood were 3.3%, 9.7%, and 10.9%, respectively. The inter-observer variabilities for the same parameters were 2.9%, 7.9%, and 12.7%, respectively. The same results were obtained by Lees and co-workers [13] and proved to be a little better for the intra-observer mean diameter calculated from four measurements of the UV (0.22 mm, respectively). Similar positive findings in reproducibility were reported by Boito et al. [14]. The coefficient of variation for the umbilical vein cross-sectional area was 6.6%, and for the time-averaged velocity it was 10.5%, resulting in a coefficient of variation of 11.9% for volume flow. The mean time required to obtain a complete set of measurements in our study was 3 min. These findings obtained in three different centers provide enough evidence to support the hypothesis that, as far as reproducibility and clinical feasibility are concerned, today's technology is able to achieve accurate measurements of the umbilical vein flow in the human fetus.

Volume Flow Values and Problems of Standardization

The specific umbilical vein flow we calculated from our findings [12] was 129 ml/min kg^±1at 20 weeks of gestation and 104 ml/min kg^±1 at 38 weeks of gestation. Boito et al. reported similar, but lower values, 117.5Ô33.6 ml/min kg^±1to 78.3Ô12.4 ml/min kg^±1for the same gestational age span [14].

Di Naro, with a similar methodology, reported values of 126.0Ô23.4 ml/kg per min at term [15]. Lees and co-workers reported [13], according to their methodology, values as high as 176 ml/min kg^±1, which are closer to the mean arterial values measured by Kunzel in 1992 (143 mm/kg min^±1) [16]. Actually, Lees et al. [13] was measuring an average of arterial and venous volume flow and Kunzel et al. [16] was measuring mean arterial flow. Accurate hemodynamic modeling of a pulsatile flow is quite complex, mostly because of problems in assessing the time-averaged mean velocity [17]. If we compare our present (108 ml/min kg^±1 at 32±41 weeks of gestation) we Fig. 30.1. a Magnified image of a straight section of the

umbilical vein. b Magnified image of the color imaging of the umbilical vein. Note how the peak velocities are skewed toward the external wall of the curved vein

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appreciate the fact that these mean values are at the same level of umbilical volume flow measured by Eik-Nes in 1982 [3] (115 ml/min kg^±1). The only difference with these ªhistoricalº reports is the time required to obtain these measurements, and their reproducibility. Other methodologies had been tested for the same purpose by Kiserud [18] and Chantraine et al. [19]. This latter work represents newer techno- logical possibilities and at the same time reminds us of the quest for standardization of non-invasive flow measurements. We still hold the opinion that given the limitations of Doppler technology, the true mean instantaneous velocity should be derived by the peak velocity times the coefficient derived by the general model of flow. According to Pennati et al. [20] this coefficient should be set at a value of 0.61. This re- port induced us to revise the values we reported in 1999 [12] just by increasing them by 18%. This means that the volume flow in the umbilical vein at 38 weeks of gestation is 123 ml/min kg^±1 instead of 104 ml/min kg^±1. In this brief analysis we have met many methodologies that differ from our simple diameter-peak velocity interrogation: off-line measurement of cross-sectional area, software-dependent measurements of time-averaged mean velocity, mean values of venous and arterial flow measurements, and non-Doppler flow measurements. It is quite evident from published methodologies and results that the variability in measurements between centers is not stochastic; rather it is systematic, depending on the different methodologies adopted. So far, the simpler the better is our preferred choice.

Comparison Between Non-Invasive Doppler Volume Flow Values

and Traditional Experimental Studies

The simple ªdiameter-peak velocity ´ 0.5º methodology was applied to the two veins of fetal lambs versus historical measurements of flow obtained with invasive technique [12]. Gestational age and fetal weights were not different between the animals studied by Doppler technique (129.6Ô2.8 days, 2.75Ô0.26 kg, respectively) and steady-state data (131.6Ô4.1 days, 2.94Ô0.68, respectively). Variability between the groups was similar (f test; p=0.138). No significant differences were detected between the Doppler and diffusion technique groups for umbilical venous flow (210.8Ô18.8 and 205.7Ô38.5 ml/min kg^±1; p=0.881).

A second study was then performed on the same set of seven animals [21]. Ultrasound Doppler and steady-state diffusion technique yielded virtually identical results (207Ô9 vs 208Ô7 ml/min kg^±1). A serendipitous result of that study was that the venous flow in each one of the two veins of the lambwas strictly correlated with the weight of the cotyledons

serving each vein. The accuracy of volume flow measurements was tested by Di Naro and co-workers [15]

on human fetuses with different characteristics of the umbilical cord, normal coiled cord, and non-coiled lean cord, assuming and proving that the latter is a less favorable hemodynamic condition for umbilical circulation.

From Umbilical Flow Volume Mea- surements to Fetal Pathophysiology

The Relationship of Umbilical Vein Blood Flow to Growth Parameters

in the Human Fetus

According to our reported study, umbilical blood flow increased exponentially throughout pregnancy from 63 ml/min at 20 weeks to 373 ml/min at 38 weeks [12]. By means of a different methodology, Boito and co-workers reported an increased volume flow from 33 ml/min at 20 weeks to 221 ml/min at 36 weeks of gestation [14]. When these absolute values are con- verted into weight-specific values, as reported above, the higher values become lower. In general, the esti- mation of fetal weight has a possible error of approxi- mately Ô10% in 68% of cases. This error can even be larger in growth-restricted or macrosomic fetuses in which there is a change in the volumetric proportion between head and abdomen. As a result, expressing blood flow per kilogram estimated fetal weight intro- duces unnecessary errors and may obscure underly- ing pathophysiology. In contrast, the abdominal circumference as measured by ultrasound has been shown in many studies to serve as an early and sensi- tive biometric indicator of fetal growth restriction.

Reporting data both as weight-specific values and abdominal or head circumference-specific values could help to compare ªreal measurements,º and hopefully it could better serve the purpose of using flow volume in clinical practice.

Umbilical Vein Blood Flow and Abnormal Fetal Growth

The next step, which is relatively independent from systematic differences caused by various methodologies, is to observe what is happening under varied intrauterine conditions of the fetus and of the placenta.

According to Kiserud and co-workers maternal hypoxemia on 12 pregnant sheep caused significantly reduced maximum and weighted mean blood velocity [22]. According to Padoan and co-workers at the Uni- versity of Colorado Health Sciences Center, weight- specific umbilical venous flow is significantly reduced in fetal lambs affected by heath stress chronic growth

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restriction compared with normal fetuses of comparable gestational age (129.4Ô14.8 vs 176.4Ô13.3 ml/

min kg^±1; p<0.05) and is correlated to pO2(10.9Ô1.2 vs 19.1Ô0.7; p<0.001) [23].

Obviously, when comparing normal fetuses to growth-restricted fetuses, it is important that the flow be related to some index of tissue mass, and not to gestational age, as is the case for qualitative waveform indices in the human ªsmallº fetuses. This can be done by calculating an estimated fetal weight or from some other anthropomorphic measurement directly derived by ultrasound images. In our experience [24]

umbilical volume flow in growth-restricted fetuses is reduced on a weight basis (Fig. 30.2). If we consider only those growth-restricted fetuses delivered without ominous heart rate signs (mean gestational age 32Ô4;

mean weight 1265Ô424 g) weight-specific umbilical flow (ml/min kg^±1) was significantly lower than con- trols of comparable gestational age (98.4 Ô 19.1 vs 117.1 Ô 29.9; p<0.001). A much larger difference was observed when flow measurements were obtained on growth-restricted fetuses with an abnormal heart rate, just before elective delivery (mean gestational age 29Ô3 weeks; mean weight 962Ô334 g; 63.0Ô22.1 vs 124.0Ô30.3 ml/min kg^±1; p<0.001). Boito and co- workers reported umbilical volume flows per kilogram fetal weight below the normal range in 21 of 33 growth-restricted fetuses [14]. These findings were replicated by the same group on a second series [25]

of 23 growth-restricted fetuses who showed a significant lower weight-specific flow compared with con- trols (59.6 vs 104.7 ml/min kg^±1; p<0.001).

A broader impact on the understanding of fetal physiology under a condition of growth restriction

due to poor placental development can be derived by umbilical flow volume measurements when cross-sectional measurements obtained at a late stage of growth restriction, i.e., just before elective premature delivery, are highlighted by longitudinal observation from the early stage of the disease. The findings reported by Rigano and co-workers [26] showed that UV weight-specific flow (ml/min kg^±1) was reduced at the time of patient enrolment in 71.4% (15 of 21 IUGR fetuses) of the study population. By the time of delivery, 76.2% of the IUGR fetuses had UV weight- specific flow less than the 10th percentile. Figure 30.3 shows longitudinal umbilical flow volumes in growth- restricted fetuses per unit fetal weight with abnormal umbilical pulsatility index (PI), and with normal umbilical PI. These longitudinal observations suggest that this reduction is present weeks before heart rate abnormalities, this means that fetal±placental flow has its main impact on fetal metabolism. These data were replicated by Di Naro and co-workers [27]. De- spite the different methodology and slightly different absolute value, the same message of early reduction was confirmed.

Diagnostic Usage of Umbilical Vein Blood Flow in Growth-Restricted Fetuses

Differences between normal and growth-restricted fetuses could be more reproducibly assessed if the head or the abdominal circumference were used directly instead of ultrasound assessment of fetal weight. Fig- ure 30.4 shows the same volume flow measurements as Fig. 30.3. In this analysis absolute flow values are Fig. 30.2. Umbilical venous flow per unit weight (ml/min

kg^±1). Growth-restricted fetuses with abnormal umbilical arterial pulsatility index (triangles). Growth-restricted fetuses with normal umbilical arterial pulsatility index (circles). The 2nd, 5th, 50th, 95th, and 98th percentiles of normal reference values

Fig. 30.3. Longitudinal assessment of umbilical venous flow per unit weight (ml/min kg^±1). Growth-restricted fetuses with abnormal umbilical arterial pulsatility index (full circles). Growth-restricted fetuses with normal umbilical arterial pulsatility index (empty circles). The 2nd, 5th, 50th, 95th, and 98th percentiles of normal reference values

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normalized by the head circumference (ml/min mm^±1).

The advantage of this simplified normalization stems also from the fact that fetal head is an area of prefer- ential distribution of flow and growth in the deprived fetus [28]; therefore, the use of this part of the fetal body as an index of fetal body mass improves the sensitivity of flow assessment in asymmetrically growth-restricted fetuses.

The increase in flow volume throughout gestation in normal fetuses is accounted for mainly by growth of the umbilical fetal vessels. The diameter of the vein in- creases from 4.1 to 8.3 mm, which would lead to a four- fold increase in cross-sectional area, whereas the velocity increased only 20% from 0.08 m/s at 20 weeks to 0.10 m/s at 38 weeks [12]. When blood velocity and diameter is normalized for fetal mass, an interesting result that can be observed in growth-restricted fetuses is that the diameter in small fetuses is not narrower than that of normal fetuses of comparable mass, whereas the main variable to decrease is blood velocity (Fig. 30.5). According to these data velocity itself could be used as a simple diagnostic test in growth-restricted fetuses. According to fetal sheep experiments [29] pres- sures and flow velocities are inversely related in the venous in-flow tract from the umbilical vein to the ductus venosus and inferior vena cava, this finding brings in both a diagnostic potential and a pathophysiological variable of interest.

In the same paper by Boito and co-workers, else- where quoted [25], a complex set of ultrasound volumetric measurements was performed on the head and

on the abdomen of restricted and normal fetuses and a significant (p<0.001) inverse relationship was observed between fetal weight-related umbilical venous volume flow and fetal brain/liver volume ratio. The same diagnostic-oriented usage of umbilical venous flow was adopted by Tchirikov and co-workers [30].

In their reported experience the ratio between weight-specific umbilical vein blood volume (ml/min kg^±1) and umbilical artery PI was a better predictor of poor fetal outcome than umbilical arterial PI alone.

Redistribution of Umbilical Flow in Fetal Liver

Umbilical arterial qualitative velocimetry has probably reached its maximum clinical value. Its usage in fetal medicine is now a key criterion to differentiate severe growth-restricted fetuses from less severe forms and other diseases causing growth restriction.

Umbilical volume flow measurements help us to better understand the pathophysiology of growth restriction. What happens under conditions of chronic hypoxia in the human fetus? From animal experimental studies we know that ductal dilatation sustained by the presence of an active sphincter regulation is the hypothesized mechanism allowing the fetal adapta- tion to the hypoxia [31]. This interpretation was confirmed in a recent experimental study in fetal sheep Fig. 30.4. Longitudinal assessment of umbilical venous

flow per head circumference (ml/min mm^±1). Growth-restricted fetuses with abnormal umbilical arterial pulsatility index (full circles). Growth-restricted fetuses with normal umbilical arterial pulsatility index (empty circles). The 2nd, 5th, 50th, 95th, and 98th percentiles of normal reference values. HC head circumference

Fig. 30.5. Umbilical venous mean velocity per unit head circumference (ml/min mm^±1). Growth-restricted fetuses with abnormal umbilical arterial pulsatility index (full circles). Growth-restricted fetuses with normal umbilical arterial pulsatility index (empty circles). The 2nd, 5th, 50th, 95th, and 98th percentiles of normal reference values. HC head circumference

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by Kiserud and co-workers [32]. Their data showed that induced hypoxemia determined a significant dilatation of the isthmus of DV. In 1998 our group reported the first suggestion of in vivo ductal dilatation in two IUGR human fetuses examined for a pro- longed period of time [33] and more recently such findings were confirmed on a larger series of growth- restricted fetuses [11, 34, 35]. Reduction in umbilical vein flow volume and an increase in the ductal shunt- ing determines a severe deprivation of substrate in the right liver lobe initiating a severe organ failure, the prevention of this damage can prove to be of great impact on proper timing of delivery in severe growth-restricted fetuses.

For clinical usage this set of knowledge can be used with a criteria of feasibility: the simpler the better. Since the reduction of flow in the umbilical vein is determined by a reduction in velocity and not by the diameter of the vessel [24], only the measurement of velocity only could be used. If volume flow per unit fetal weight is influenced by errors in weight es- timation, why do we not use volume flow per unit head circumference? If we know that the ductal a- wave is determined by dilatation of the inlet [11, 33, 34], the diameter of the ductus only could be checked when qualitative indices change without resorting to complex velocity measurements.

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