Blood flow volume of uterine arteries in human pregnancies determined using 3D and bi-dimensional imaging, angio-Doppler, and fluid-dynamic modeling

Article Outline

• Abstract
• 1. Introduction
• 2. Materials and methods
  • 2.1. Study population
  • 2.2. Ultrasonic procedures
    • 2.2.1. Anatomical and biometrical examination
    • 2.2.2. Doppler interrogation of uterine vessels
    • 2.2.3. Mathematical model of the uterine arterial velocity profiles
  • 2.3. Statistics
• 3. Results
• 4. Discussion
• Appendix. Supplementary data
• References
• Copyright

Abstract 

The primary aim of this pilot study was to study uterine artery (UtA) blood flow volume in uneventful human pregnancies delivered at term, at mid and late gestation by means of 3D and bi-dimensional ultrasound imaging with angio-Doppler combined with fluid-dynamic modeling. Secondary aims were to correlate flow volume to placental site and to UtA Pulsatility Index (PI).

Women with singleton, low-risk pregnancies were examined at mid and late gestation. The structure and course of the uterine artery (UtA) was studied in each patient by means of 3D-angio-Doppler and included vessel diameter D, blood flow velocity and PI (measured along the UtA). Fetal weight estimation and placental insertion site were assessed by ultrasound. A robust fluid-dynamic modeling was applied to calculate absolute flow and flow per unit fetal weight.

Mean UtA diameter and blood flow velocity increased significantly (p < 0.0001) from mid-gestation to late gestation from 2.6 mm and 67.5 cm/s, to 3.0 mm and 85.3 cm/s, respectively, yielding an increasing absolute flow troughout gestation. h coefficient, derived by fluid-dynamic modeling to calculate mean velocity, increased significantly from 0.52 at mid-gestation to 0.57 at late gestation. UtA blood flow volume ml/min/kg-fetal weight was significantly higher at mid-gestation than at late gestation (535 ml/min/kg vs 193 ml/min/kg; p < 0.0001). In cases with strictly lateral placentas the ipsilateral UtA accommodates at mid and late gestation 63% and 67% of the total UtA flow. In central placentas UtA flow was evenly distributed between the two vessels. An inverse correlation was observed between PI and blood flow volume ml/min/kg (Pearson's coefficient r = −0.54).

Our work confirms the technological and methodological limitations in the measurement of uterine artery blood flow. However, Doppler measurements supported by three-dimensional angio imaging of the uterine vessel, high resolution imaging and diameter measurement, and a robust mathematical model of local circulation adds a genuine new area of investigation into human uterine circulation during pregnancy.

Keywords: Blood flow volume, Uterine artery, Pregnancy, Ultrasound, Doppler velocimetry

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1. Introduction 

Utero–placental blood flow provides nutrients and oxygen for feto–placental growth. Trophoblast migration into the spiral arteries wall leads to larger lumen diameter, which combine to reduce impedance to flow into the developing intervillous space. Changes at the cellular level and the impact of progressive shear stress due to increased flow dramatically modify the blood volume accommodated by the uterine arteries with each cardiac cycle. Evidence of a correlation between placental lesions and increased impedance to utero–placental flow has been observed consistently in complicated human pregnancies by Doppler velocimetry [1], [2], [3], [4]. Despite a robust pathological background and the extensive clinical usage of uterine Doppler velocimetry in high risk pregnancies, only a few studies have attempted the quantification of actual blood flow volume. Table 1 briefly describes the different techniques to calculate uterine blood flow volume and the wide range of results obtained, which were initially described in the 1950s. With up-dated technology reproducibility of ultrasound and Doppler measurements for blood flow volume does not seem to pose a major limitation [11]. The major challenge not thoroughly addressed in previously published works concerns the evaluation of the mean spatial blood velocity [12]. An efficient and robust solution is to deduce the mean spatial velocity by scaling the maximum velocity measured in the investigated area with a Spatial Velocity Distribution Coefficient [13], [14]. The value of this methodology is enhanced by three-dimensional imaging and high resolution of sonographic imaging of uterine vessels. Its application could eventually help explain the poor specificity of impedance indices of the uterine arteries. The primary aim of this study was to apply a fluid-dynamic modeling to assess the mean spatial velocity in the uterine artery (UtA) necessary to calculate the blood flow volume in a cohort of uncomplicated pregnancies at mid-gestation and in the third trimester. The secondary aim was to correlate flow volume to strictly defined placental site and to determine the correlation between UtA blood flow volume and UtA pulsatility index (PI).

Table 1. Different techniques adopted to calculate uterine blood flow volume and results reported from 1955 to 2007.

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2. Materials and methods 

2.1. Study population 

Women with singleton, low-risk, and uncomplicated pregnancies scheduled for routine ultrasound screening examinations were asked to participate in this prospective study. According to the Italian National Health Service, a routine ultrasound examination is offered at approximately 20 (mid-gestation) and at third trimester around 32 weeks of gestation. The following demographic, sonographic and Doppler findings were considered as inclusion criteria: Caucasian ethnicity, low-risk singleton pregnancies, sonographic assessment of gestational age in the first trimester, normal mean UtA PI at the time of first examination and throughout gestation, maternal blood pressure within the normal ranges until delivery. Exclusion criteria were: chromosomal abnormality, structural malformations, and maternal chronic diseases; obstetrical history with gestational hypertension preeclampsia, HELLP syndrome, IUGR, abruptio placentae, gestational diabetes, unexplained fetal loss/intrauterine fetal death, tobacco/alcohol use. In addition to this, cases with an unclear vessel anatomy or a markedly twisted vessel were excluded. An informed consent for participation in the study was obtained from each eligible patient. Gestational age at delivery, birth weight, neonatal outcome were recorded. Seventy-one singleton normal pregnancies were recruited for the study.

2.2. Ultrasonic procedures 

All examinations were performed (S.R., S.B., A.P.) between 9.00 and 1:00 with a maximum examination length set at 45 min. A learning curve was observed for the duration of the examination along the time period of this study, especially as regards the assessment of the vessels anatomy. Uterine artery blood flow volume measurements on each side were performed with the woman in a semi-recumbent position.

The anatomy of the UtA and its corporal and cervical branches was studied in each patient by means of 3D-angio-Doppler in order to identify the UtA before any visible vascular division (Fig. 1a) (Voluson Expert General Electric Healthcare). Vessel diameter D, blood flow velocity and PI were measured along the UtA, approximately 15 mm upstream to vessel bifurcation on the common trunk of the uterine artery. Measurements were taken for both right and left UtA. Diameters were measured on a perpendicular B-mode view of the longitudinal vessel section, at the maximum magnification. The lumen of the vessel was visualized by the color power angiography and the diameter was measured on a gray-scale image after reducing the color box, by placing the calipers at the inner edges of the vessel itself at the specular reflection (Fig. 1b). The average of three repeated measurements of vessel diameter was served as the final diameter. A lateral placenta was defined when the mid–sagital plane of the uterus was not reached by the medial edge of the placenta.

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• Fig. 1 

  a) 3D-angio-Doppler imaging of UtA, approximately 15 mm upstream to vessel bifurcation on the common trunk of the uterine artery at the level of the cross-over external iliac vessels. After the 3D geometry of the vessel and the spot (∅) where to measure the uterine artery was visualized the sonologist moved the probe in order to put the uterine vessel on the 2D plane where the combination of tissue imaging and angio imaging provides the best view of the spot where to measure the diameter. b) UtA diameter measured along the common UtA trunk (∅ on Fig. 1a) UtA was evidenced by angio-Doppler box and calipers were placed at the inner edges of the vessel on B-mode imaging, after partial removal of the box. c) UtA blood flow velocity measurement. After the diameter is measured, the transabdominal probe is rotated approximately 90° on the ideal fulcrum of the spot were the diameter was measured (∅) to obtain a Doppler beam angle <30 and as closest as possible to 0°.

UtA blood flow velocity and PI were measured with a Doppler beam angle <30 (Fig. 1c). Angular correction of velocity was performed. The time-average maximum velocity along the cardiac cycle (V_max) and the mean PI over 3–5 cardiac cycles were utilized. The heart rate was also recorded, as required for the evaluation of Womersley number (see Appendix). The blood flow rate (ml/min) through each UtA was calculated according to the formula . (see below for definitions). UtA volume flow was calculated separately for each the right and left uterine artery and total UtA volume flow was calculated as the sum of the flow from both vessels.

Fetal Biometry. Routine fetal biometry (biparietal diameter, head and abdominal circumference, and femur length) and placental site were recorded after completion of uterine artery measurements bilaterally. Fetal weight was estimated according to Hadlock's formula [15].

The UtA in the tract between its origin from the internal iliac artery and the cervical–corporal bifurcation usually shows a roughly straight path with constant diameter and no branching, and its flow in normal pregnancies is a pulsatile, forward, laminar flow [16]. Along such a vessel, within the so-called ‘entrance region’, the spatial velocity profile undergoes development from an initial shape at the inlet to a fully developed profile some distance downstream [17]. The spatial velocity profile of arterial blood flow along the UtA and corresponding Spatial Velocity Distribution Coefficient (h) were calculated on the basis of Reynolds and Womersley numbers, two dimensionless quantities describing the vessel hemodynamics. These were specifically evaluated for each right and left uterine arterial vessel on the basis of the measured diameters (D), blood time-averaged maximum velocities and heart rate, while mean values obtained in pregnant women [18] were used for maternal blood properties (3.3 cP and 1.06 g/cm³ for the viscosity and density, respectively). Moreover, the distance (L) from the internal iliac artery to the Doppler sampling site is expected to be between 3 and 5 cm, though the exact value for a specific UtA is not known since visualization of the UtA origin is not always achievable. A preliminary analysis showed that this L uncertainness has a negligible impact on the uterine h coefficient calculations, suggesting the use of a fixed value of 4 cm.

Finally, from the knowledge of L, D, Reynolds and Womersley numbers the h coefficient was evaluated for each specific case (see Appendix). This coefficient was used to scale down the measured time-averaged maximum velocity to a calculated time-averaged mean velocity. A similar approach was previously applied to evaluate spatial velocity profiles in mouse embryonic aorta [19].

2.3. Statistics 

Univariable logistic analysis was performed using STATA (version 8 Statacorp, College station, Texas, USA). Non-parametric statistics were used to describe and compare sets of measurements not normally distributed in mid-gestation and third trimester and between left and right uterine vessels (ANOVA and Spearman Correlation). To describe quartile distribution along gestation mid-gestation and third trimester data were analyzed as a single set of findings. The best fit regression was calculated and percentile distribution was calculated. The Pearson test after semi-logarithmic transformation was used to test the correlation between uterine flow waveform (pulsatility index) and uterine volume flow.

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3. Results 

The biometric and Doppler-velocimetric sampling of the two UtA was not achievable in 3 out of 71 examinations because of unclear vessel anatomy or markedly tortuous vessels. Two cases were excluded because of neonatal morbidity, including a condition of severe extrauterine growth restriction reported at six months. Sixty-six patients were included in the present analysis. All patients delivered at term without complications with normal neonatal weights and outcomes. Median gestational age at the time of examination at mid-gestation and in the third trimester were 21 weeks (i.q. 20–22) and 33 weeks of gestation (i.q. 31–35). Median Pulsatility Index of the UtA in the two groups were 0.89,(i.r. 0.67–1.09) and 0.63.(i.r. 0.59–0.74) respectively (p = n.s.) Median maternal age and B.M.I. of patients recruited at mid-gestation was 32 years (i.q. 30–33) and 21 (i.q. 19–21). For patients recruited at the third trimester maternal age and B.M.I. were 32 (i.q. 28–33) and 21 (19–23) respectively. The percentage of primigravide was not significantly different between the two groups (36% vs 54%). Gestational age at delivery and neonatal birth weight between the two groups were not significantly different. Patients recruited at mid-gestation were delivered at 39 weeks (i.q. 38–40) of newborns with a median weight of 3050 g (i.q. 2820–3340). Patients recruited at the third trimester were delivered at 40 weeks (i.q. 39–41) of newborns with a median weight of 3215 g (i.q. 3121–3425).

The calculated values of Reynolds (convective-to-viscous forces ratio) and Womersley (inertial-to-viscous forces ratio) numbers resulted in mean values (±sd) of 432 ± 276 and 2.21 ± 0.47, respectively. The spatial velocity distribution of h coefficients, obtained by these calculations ranged between 0.5 (parabolic-like pulsatile profiles) and 0.79 (more flat pulsatile profiles). Moreover, significantly higher values of h coefficient were obtained in third trimester (mean: 0.57 ± 0.06) than in second trimester cases (median: 0.52 ± 0.03; p < 0.0001).

Fig. 2 depicts the original findings for the absolute blood flow (ml/min) vs gestational age and also that variability increases along gestation, the calculated 5th, 10th, 90th, and 95th smoothed percentiles are reported As expected, total UtA blood flow was significantly higher in the third trimester than in mid-gestation. Mean values ± s.d. for diameter and velocity increased significantly (p < 0.0001) from 2.6 ± 0.05 mm, and 67.5 ± 24.7 cm/s, to 3.0 ± 0.05,mm and 85.3 ± 24.6 cm/s respectively.

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• Fig. 2 

  UtA absolute flow volume (ml/min) plotted on gestational age. Original findings are reported as full dots. Best fit regression (y = 2.5589x^1.456). Upper and lower continuous lines represent the 5th, 10th, 90th, and 95th percentiles.

Table 2 presents the UtA blood flow volume and its determinants (diameter and velocity) in pregnancies with lateral placenta implantation. In cases with a centrally located placenta, there were no differences in flow at mid-gestation and at third trimester between the right and left sides.

Table 2. UtA blood flow volume data in normal pregnancies with a strictly lateral placenta insertion. Ipsilateral refers to flow on the same side of the placenta. Values are expressed as median and interquartile ranges.

Fig. 3 depicts the best fit curve and the percentile smoothed curves of the original findings for blood flow per minute per kilogram (ml/min/kg) vs gestational age. In contrast to the absolute flow, there was an inverse negative relationship in the variablity of flow per unit fetal weight vs gestational age. Fig. 3 b) shows the estimated UtA blood flow volume ml/min/kg from 18 to 36 weeks of gestation. Values are reported as 10th, 50th, 90th percentile. Five cases observed longitudinally are superimposed to the plot. Median UtA blood flow volume per kg fetal weight was significantly lower in the third trimester (193.ml/min/kg, i.r.144–260) than at mid-gestation (535 ml/min/kg, i.r. 368–706)(p < 0.001).

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• Fig. 3 

  a) Uta flow expressed per kg fetal weight (ml/min/kg) plotted on gestational age. Best fit regression (y = 162188x^−1.8979). Upper and lower continuous lines represent the 5th, 10th, 90th, and 95th percentiles. Five longitudinal observations are plotted as individual lines. b) UtA blood flow volume ml/min/kg. Values are reported as 10th, 50th, 90th percentile.

Fig. 4 shows the correlation observed at mid-gestation between Pulsatility index and UtA blood flow volume. A large inverse correlation was observed between PI and blood flow volume in the UtA. (Pearson's coefficient r = −0.54).

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• Fig. 4 

  Correlation between UtA flow volume calculated in a single artery and the PI measured in the same vessel, (Pearson r = −0.53). Black dots, data point. Continuous line, best fitting regression (y = 95.696x^−1.1438). Dashed lines 25th and the 75th percentiles.

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4. Discussion 

The present pilot study reports an assessment of uterine blood flow in human pregnancies with an uneventful outcome at term. It is fair to say that there have been problems with all the attempts that have been made to measure uterine blood flow, including the present study. In addition to this the combined methodology adopted requires a long time of examination even though a learning curve was observed during the study and the maximum 45 min observed at the beginning was never reached in the second half of the study. However, we believe that the present study provides a reasonable estimate using the best of current methodology and minimizes some of the known problems with uterine artery blood flow volume measurements described below. In addition, the present study has brought out several important characteristics of uterine blood flow volume in normal pregnancies.

Firstly, while the absolute flow (ml•min⁻¹) increased from mid to late gestation, whereas the flow expressed per unit fetal weight decreased from 535 to 193 ml•min¹•kg⁻¹. In early gestation, the fetal O₂ consumption per kg is higher than at term and the proportion of conceptus mass represented by the placenta is much greater than it is in late gestation. In fact, these calculations do not take into account the placental weight which is larger than the fetus at 20 weeks gestation [19], but is equal to only 1/5 to 1/7 of fetal weight at term. One could speculate that if we prudently assume a 1:1 fetal placental weight ratio [20] at mid-gestation, the flow per unit feto–palcental weight should be recalculated as 290 ml min kg⁻¹, whereas at 33 weeks of gestation it would become approximately 180mil*min*kg⁻¹. These values are in agreement with most reported data but those by Konje [8] who measured vessels diameter with the least accurate space resolution ultrasonic techniques, i.e. angio-Doppler imaging.

Secondly, this study confirms the importance of measuring flow in both uterine arteries. In placentas strictly located on one side of the uterus, the ipsilateral uterine artery flow accounts on average for approximately 63% 67% of the total flow both at mid-gestation and at term respectively. These findings are in agreement with reported observations by Konje [8], who found only a 20% difference between vessels. This difference is indeed explained by the strict criteria adopted in this paper to define a lateral placenta. The hemodynamic dominance of the ipsilateral UtA is likely related to a lower impedance vascular bed related to cytotrophoblast invasion and related spiral artery remodeling. In pregnancies with centrally located placentas, UtA blood flow volume was similar in the two arteries, thus confirming the influence of placental proximity on UtA vascular resistances.

Thirdly, a significant correlation was observed between UtA blood flow volume and the pulsatility index of the uterine arteries. This correlation adds additional physiological background to the Doppler investigation of the uterine arteries by means of simple waveform angle independent indices and is in agreement with preliminary reports on the association between intrauterine growth restriction and reduced UtA blood flow volume [21]. Our quantitative findings observed in lateral placenta could support the view of Hernandez-Andrade E. et al. [to be re-numbered] who concluded that Doppler velocity waveforms of the uterine arteries in the prediction of placental pregnancy complications can be evaluated disregarding the placental location and a single cut-off value for the Pulstility index can be set at 1.2. We speculate that since the sum of the flow of the two arteries is not significantly affected by lateral placenta insertion a similar concept could be extended to waveform analysis were the sum of the PIs or the average of the two PI should be used. In addition to this, we could derive from the correlation between PI and blood flow volume that when the PI goes from 1.2 to 1.4, volume flow may be substantially reduced questioning the utility of volume flow measurements at these lower limits of physiology. However, given that this is speculative, the measurements of volume blood flow should not be limited to any specific cut-off as it is still at an investigative stage.

As to the wide range of UtA blood flow volumes obtained in this study at both mid and late gestation, the reasons for this could rest in many factors, some biological and some purely technical. Four possibilities are outlined and described below:

For comparison, the uterine blood flow volume at a similar gestational age (approximately 420 ml/min/kg) directly calculated from the original data of Meschia and Wallace on fetal lambs [26], [27], [28] was twice the value we measured in the present study. It is of interest to note that provided this uterine blood flow, a human fetus achieves approximately the same weight as fetal lambs at term, but in twice the duration of intrauterine growth. This could mean that the total amount of nutrients and oxygen are delivered to a human fetus in twice the time by a pipeline with half the flow rate of those supplying a sheep fetus. What remains unknown is the relationship of uterine volume blood flow to that of intervillous blood flow. Work by Burton et al. [29] addresses the physiological impact of maternal spiral artery remodeling in utero–placental blood flow. Perhaps utilization of the new approach using available technologies described in this study will provide further insight into intervillous flow, however, this goes beyond the scope or capabilities of the current study.

Limitations of the study presented in this manuscript include the lack of reproducibility studies. Certainly as this work moves forward, both inter- and intra-observer variabilities will be assessed. Another potential limitation is the lack of pathological evaluation of placenta at delivery as well as informations on placental proteins in the first trimester which could help to identify a normal placentation [30]. It is likely that provided the strict criteria of inclusion and exclusion these additional confirmation of normal placenta would not have added substantially to the study The methodologies described in this manuscript are preliminary in nature with additional work needed to refine the technique and assess reproducibility. Although the primary intent of this paper was to describe a technique of uterine flow measurement and it's use as an investigational tool to better understand the physiology of human uterine volume blood flow, the possibility of its use clinically is worthy of discussion. This clinical discussion should be centered on the value of uterine volume blood flow vs uterine indices of resistance using Doppler velocimetry. One can argue in favor of volume blood flow measurement from two standpoints. The first is that volume blood flow is more reflective of physical blood flow to the uterus, and thus more accurately portrays uterine perfusion than velocimetry (a more robust physiological measurement). Cardiologists do not rely on cardiac flow velocity waveforms alone to assess cardiac function. They focus on cardiac output, which is an assessment of volume blood flow pushed out of the heart. Secondly, volume blood flow provides more information on blood flow characteristics as it contains more physical parameters (more variables in the calculation) and one of these parameters is velocimetry itself. A couple of arguments against the use of volume blood flow is that the technique still requires further attention (as outlined in the manuscript) and that there is no accountability for the contribution of infundibulopelvic blood flow to the total uterine volume blood flow. The latter argument can also be used against velocimetry given that the literature is void of utero–ovarian velocimetry assessment.

In conclusion, our work confirms the technological and methodological limitations in the measurement of uterine volume blood flow in the uterine arteries. However, our study differs by the Doppler measurements supported by three-dimensional angio imaging of the uterine vessel, high resolution imaging and diameter measurement, and a robust mathematical model of local circulation, which provides a potentially useful technique for physiological assessment of the human uterine circulation during pregnancy. The possible role of uterine blood flow volume measurement, notwithstanding methodological bias including lack of reproducibility studies, has already proven its value in physiological studies, when tested under extreme extreme conditions such as very high altitude pregnancies [31]. The next challenge is that of mid-gestation measurements in fetuses who will later develop a condition of growth restriction. With the contribution of a more robust methodology, pregnancies at risk of IUGR based on uterine artery Doppler velocimetry impedance indices could be further investigated in future studies by assessment of blood flow volume, which help to understand the physiology of uterine circulation when abnormal uterine waveform are detected by Doppler velocimetry.

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Appendix. Supplementary data 

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