European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 275–279

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Doppler parameters of the maternal hepatic artery blood flow in normal pregnancy: maternal hepatic artery blood flow in normal pregnancy Vesna D. Mandic-Markovic a,*, Zeljko M. Mikovic a, Milan K. Djukic a, Mladenko D. Vasiljevic a, Goran Lj Jankovic b a b

School of Medicine, University of Belgrade, University Clinic for Gynecology and Obstetrics ‘‘Narodni front’’, Belgrade, Serbia School of Medicine, University of Belgrade, Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, Belgrade, Serbia

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 March 2014 Received in revised form 24 July 2014 Accepted 7 August 2014

Objective: Objective of our study was to evaluate changes in Doppler resistance indices in the common hepatic artery during normal pregnancy. Study design: Cross-sectional study included 210 healthy pregnant women gestational age 6–40 weeks, 40 healthy non-pregnant women and 30 women after delivery. We divided all pregnant women by pregnancy trimester. We registered pulsatility index (PI) and resistive index (RI) in the common hepatic artery and compared the evaluated values among non-pregnant women and women in first, second and third trimester and post partum and tested correlation of both parameters with gestational age. Statistical analysis was done by Chi square test, one-way ANOVA followed by post-hoc test and twotailed Pearson and Spearman correlation. The difference was considered to be significant if p < 0.05. Results: We found lower values of PI and RI in the third trimester compared to control group and first and second trimester (p < 0.01). There is negative correlation between the values of PI and RI with the gestation (p < 0.01). Conclusion: Hepatic artery resistance indices decrease during the third trimester of pregnancy. This decrease may be the result of systemic arterial vasodilatation in normal pregnancy. The arterial resistance indices may be more useful for the evaluation of liver blood flow over the total blood flow as they are more reliable, being angle independent, easier to obtain, reflect vascular changes and might help in quick orientation about liver blood flow in pregnancies complicated by preeclampsia and HELLP syndrome. Our study is a pilot one, and further studies are needed to establish nomograms for the PI and RI during the gestation. ß 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Liver Maternal Common hepatic artery Doppler Pregnancy

Introduction Successful pregnancy outcome results from intense arteriolar vasodilatation in the maternal circulation [1]. The application of Doppler ultrasound (US) for the evaluation of maternal circulatory changes could be useful in the intensive follow up of high-risk pregnancies with preeclampsia. In pregnant women the uterine circulation was evaluated first and has become standard US examination for the prediction of preeclampsia. Other vascular beds that may be of interest during pregnancy are those also affected

* Corresponding author. Tel.: +381658181829. E-mail address: [email protected] (V.D. Mandic-Markovic). http://dx.doi.org/10.1016/j.ejogrb.2014.08.010 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.

in preeclampsia—cerebral, renal and liver circulations. The liver is usually affected in severe preeclampsia in the form of HELLP syndrome, which is one of the most severe acute conditions of pregnancy [2]. Early detection of hepatic disturbance in preeclampsia may include Doppler evaluation of liver circulation [3]. However, the liver circulation has to be evaluated in normal pregnancy, so that comparison with normal blood flow could be made in potentially hazardous conditions. Liver circulation is unique due to dual perfusion and the phenomenon of interaction between blood streams. Until now, only the absolute values of the liver circulation have been evaluated in the normal pregnancies. Mannell and Taylor, by catheterization of hepatic vein, stated that there are no changes in hepatic blood flow during pregnancy [4], while Nakai et al. by Doppler measurements

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demonstrated that the hepatic perfusion increases during the third trimester and that the major determinant of the increase is the portal venous flow, while the hepatic arterial flow remains unchanged [5]. Hepatic artery may be more significant than hepatic venous circulation, as vascular changes in preeclampsia include mostly arteries. The measurement of the total liver blood flow requires calculation of the cross section of the artery and measurement of the angle-corrected velocity, which is not always easy to accomplish. Hepatic artery is not always easy to locate because it has a rather small diameter, is Doppler angle dependent, so blood flow velocities may be measured at an inappropriate beam angle, and their values cannot always be estimated as absolute [6,7]. By contrast, resistance indices, such as pulsatility and resistive index are angle independent, easy to obtain, and may very well reflect potential vasodilatation that are expected in normal pregnancy and vasoconstriction seen in preeclampsia [8–10]. As the measurement of the total liver blood flow may be time-consuming, sometimes difficult to be measured, and, as the aim of our study was to find the best way to evaluate hepatic liver blood flow, we decided to measure hepatic artery vascular resistance indices— pulsatility (Pi) and resistive index (Ri) that are angle independent. Therefore, we decided to evaluate hepatic arterial circulation by measuring resistance indices. Those indices do not reflect total liver blood flow, they are relative values of the perfusion pressure and intrahepatic vascular resistance. The objective of our study was to evaluate changes in resistance indices in the common hepatic artery depending on gestational age and arterial blood pressure by comparing the values during the pregnancy with the values in non-pregnant women and after delivery. Materials and methods Clinical cross-sectional study included 210 healthy pregnant women between 6 and 40 weeks (wks) and 40 healthy nonpregnant women. There was no previous history of any chronic disease in all the cases (essential hypertension, diabetes mellitus, liver, renal or cardiac disease). All the pregnancies were single with no presence of gestational hypertension or preeclampsia. Institutional approval for the study was granted by The Clinics Ethics Committee in accordance with internationally accepted ethical standards (The Helsinki Declaration of 1964, as revised in 1975, 1983 and 1989), and each patient had signed the informed consent form for the participation in this study. We registered gestational age, maternal age, parity and arterial blood pressure. Gestational age was calculated from the last menstrual period and confirmed by first trimester ultrasound. Arterial liver blood flow was evaluated by measuring common hepatic artery (CHA) by pulsed Doppler ultrasound (VOLUSON EXPERT PRO with a 3.5 MHz convex transducer). All the measurements were done after at least 6 h of fasting and 10 min rest. The subjects were lying in the supine position and instructed to suspend respiration during measurements. The transducer was placed in subxiphoid space, immediately under the diaphragm, angled toward the liver, where the celiac trunk’s bifurcation into the splenic and common hepatic artery is visualized. CHA was seen in its longitudinal axis; the sample gate was placed over the lumen of the artery and velocity waveform was recorded, Fig. 1. At least three similar sequential Doppler waveforms were measured. We registered pulsatility index (PI) and resistive index (RI) in the common hepatic artery. Both indices were calculated by original computer software. During the survey, among the pregnant subjects, three showed signs of supine hypotensive syndrome, five were unable to hold their breath long enough, and in 8 inadequate Doppler signals were obtained because of obesity. Those 16 subjects were excluded and

Fig. 1. Doppler waveform of the common hepatic artery (CHA).

194 pregnant women completed the study. A total of 194 pregnant women who finished the study were divided according to pregnancy trimesters. There were 30 women in the first trimester group; 82 in the second trimester group; and 82 in the third trimester group. We evaluated 30 women after delivery from the third trimester group. We compared the values between the subject who were not pregnant and pregnant women in the first, second and third trimester of pregnancy and those evaluated postpartum as well. We made the correlation curves with gestational weeks for both evaluated parameters. For the statistical analysis we used Chi square test, one way ANOVA followed by post-hoc test and two-tailed Pearson and Spearman correlation. The difference was considered to be significant if p < 0.05. Before initiating the study all the investigators made a consensus about the method of measurements and decided that two, the most experienced investigators (VM and GJ) do all the measurements. We calculated intraobserver and interobserver reproducibility by using intraclass correlation coefficient—Ri. The Ri was derived from twoway analysis of variance in which the repeated measurements and subjects as factors. The formula used to calculate the Ri was (MSS MSE)/((MSS + (k 1)MSE) + k(MSO MSE)/n), where MSS is the mean squared variation between subjects; MSO, the mean squared variation between repeated measurements; MSE, the residual mean squared; k, the number of repeated measurements; and n, the number of subjects. The agreement was only considered acceptable from a clinical point of view when the Ri value was 0.60. Results There were no significant differences between the groups in the maternal age (p = 0.086) and parity (p = 0.651). Both systolic (p = 0.010) and diastolic (p = 0.022) blood pressures were significantly lower in the second and third trimester group, Table 1. We found statistically high significant difference in the values of PI (p = 0.00) and RI (p = 0.00) between the groups; the both indices being significantly lower during the third trimester, Table 2. We didn’t observe the presence of correlation between evaluated parameters and the parity (PI, p = 0.938; RI, p = 0.991), maternal age (PI, p = 0.366; RI, p = 0.793), nor the values of systolic (PI, p = 0.314; RI, p = 0.137) and diastolic blood pressure (PI, p = 0.894; RI, p > 0.120). There is a negative correlation between the values of PI (p = 0.000) and RI (p = 0.000) with the gestational weeks, Graphics 1 and 2.

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Table 1 Maternal age, parity and systolic and diastolic arterial blood pressure in the groups of non-pregnant, pregnant women during first, second and third trimester and after delivery. Non pregnant n = 40 Maternal age (years) Parity— nulipara Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) * §

29.90  6.172 113.30  13.10 76.500  6.228

First trimester n = 30 (%)

Second trimester n = 82 (%)

Third trimester n = 82 (%)

Post partum n = 30 (%)

27.95  9.064 13 (43.3) 111.55  13.19 76.250  7.684

27.51  6.005 40 (48.8) 104.90  14.23* 71.012  8.573§

27.98  7.505 38 (46.3) 108.96  13.49 73.207  7.649

29.23  6.637 14 (46.7) 107.74  12.89 72.26  9.384

p < 0.05. p < 0.01.

Interobserver variability was good for both PI and RI (RPI—0.69; RRI—0.68). Intraobserver variability was also good for both PI (Ri = 0.63) and RI (Ri = 0.67). Thus, both interobserver and intraobserver reproducibility of blood flow measurements were clinically acceptable in this study.

Comment Limited number of studies evaluated liver blood flow during uncomplicated pregnancy. The most important one was by Nakai et al. who measured the total liver blood flow by pulsed Doppler and calculated the flow volume in the hepatic artery and portal vein and found that liver blood flow is increased during the third trimester (up to the 160%), but on the account of increased flow through the portal vein (up to 150%), with unchanged flow through the hepatic artery [5]. In their study Clapp et al. report that portal vein blood flow increases from the first trimester, and that in the third trimester during exercise significantly decreases [11]. While portal vein has a continuous flow with slight pulsatility, and the measurements are valid when mean flow velocities are used [12], arterial blood flow in hepatic artery is often difficult to measure adequately because hepatic artery has a rather small diameter and flow velocity waveform is often found at an inappropriate beam angle. As total liver blood flow is sometimes very difficult to measure, and as the aim of our study was to find the best way to evaluate hepatic liver blood flow, we decided to measure hepatic artery vascular resistance indices–pulsatility (Pi) and resistive index (Ri) that are angle independent. Those indices do not reflect total liver blood flow. They are relative values of the perfusion pressure and intrahepatic vascular resistance. Both Pi and Ri increase with higher arterial resistance. Pi is different from Ri in that it uses mean velocity instead of peak velocity as its denominator. Pi is superior to Ri because Ri can be maximum 1.0, while Pi may have wider spectrum, and, therefore, be more precise in the cases of small diastolic velocity when arterial resistance is extremely high. [13] The liver blood flow, especially portal blood flow, is influenced by various states, such as meal, respiration and

exercise [11,14–16]. In our study we avoided those conditions by uniform measurement. Our results show that there is a significant difference in the values of PI and RI in hepatic artery between the third trimester and non-pregnant state and first two trimesters. The negative correlation of PI and RI and gestational weeks was shown. The normal hepatic arterial system has low resistance flow characteristics, and in fasting healthy subjects Ri was reported between 0.6 and 0.7, while values above 0.8 are considered to be high. Pi values may vary, but usually are under 1.5 [9]. In our subjects we found normal values during the whole pregnancy, but they were significantly higher in the first than in the third trimester. The liver blood flow was first evaluated by Mannell and Taylor more than sixty years ago by catheterization of hepatic vein who had showed that liver blood flow remains constant during the pregnancy [4]. As we didn’t measure total liver blood flow, our results are not comparable with cited article. Nakai et al. report that Doppler indices in hepatic artery remained unchanged during pregnancy [5]. We consider our result more valuable in that segment, because Nakai et al. measured only Ri, while we assessed both Pi and RI. We, also, evaluated larger number of subjects, both pregnant (194 vs 67) and non-pregnant (40 vs 22). Oosterkhof in a small study of eleven subjects, didn’t find any changes in pulsatility

Table 2 The mean values and standard deviation of the hepatic artery pulsatility and resistive index in the groups of non-pregnant, pregnant women during first, second and third trimester and after delivery. GROUP

PI

RI

Non-pregnant N = 40 First trimester N = 30 Second trimester N = 82 Third trimester N = 82 After delivery N = 30

1.38  0.28 1.30  0.33 1.29  0.27 1.09  0.23* 1.19  0.29

0.70  0.08 0.70  0.09 0.69  0.08 0.64  0.08* 0.67  0.08

PI—hepatic artery pulsatility index. RI—hepatic artery resistive index. * p < 0.001.

Graphic 1. The correlation between the hepatic artery pulsatility index and gestation: PI = 1.44 + 0.01  GW; linear correlation r = 0.11; rang correlation r = 0.356 p = 0.000; Beta = 0.356; t = 5.132 p = 0.000; HAPI—hepatic artery pulsatility index; GW—gestational week.

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Condensation Hepatic artery pulsatility and resistive indices decrease during the third trimester of normal pregnancy as a result of systemic arterial vasodilatation. Details of ethics approval The Ethics Committee of The University Clinic for Gynecology and Obstetrics ‘‘Narodni front’’ (23.03.2008., del. No 12/1) granted institutional approval for the study in accordance with internationally accepted ethical standards (The Helsinki Declaration of 1964, as revised in 1975, 1983 and 1989) and each patient had signed the informed consent form. Funding No external funding was required for this study. Conflict of interest statement No potential conflicts of interest relevant to this article were reported. Graphic 2. The correlation between the hepatic artery resistive index and gestation: RI = 0.74 + 0.00  GW; linear correlation r = 0.11; Rang correlation r = 0.339 p = 0.000; Beta = 0.339; t = 4.857 p = 0.000; HARI—hepatic artery resistive index; GW—gestational week.

Acknowledgements This work was supported by grant 173014 from the Ministry of Science, Serbia. References

index in the third trimester of pregnancy [16]. The main objection to their results, by the fact that small number of participants was considered, is that they didn’t compare values during the third trimester with the values from the second and first trimester. The significant decrease in resistance indices in hepatic artery may result rather from physiological changes in arterial blood vessels during the pregnancy and decreased vascular resistance from increased blood flow. We didn’t observe any correlation between the evaluated parameters of arterial liver blood flow and the values of systolic and diastolic blood pressure. Nakai et al. found no correlation of portal vein blood flow with the arterial blood pressure, while positive correlation of CHA blood flow and diastolic blood pressure was observed [5]. The lack of correlation between the resistance indices and blood pressure can be explained by the fact that the values of blood pressure do not influence the vessel impendance. The hepatic blood flow measurement may be extremely important in prediction and evaluation of women with preeclampsia and HELLP syndrome, which has been done in few studies with limited number of participants [3,17–19]. All of those studies evaluated total blood flow in hepatic artery and portal vein, which sometimes may be difficult, especially in the third trimester. We suggest that hepatic artery Doppler indices may be more useful in quick orientation of potentially altered liver circulation in preeclamptic patients. Our study is a pilot one, and further studies are needed to establish nomograms for the PI and RI during the gestation. We may conclude that hepatic artery resistance indices are decreased during the third trimester of pregnancy. This decrease may be the result of systemic arterial vasodilatation in normal pregnancy. The arterial resistance indices may be more useful for the evaluation of liver blood flow over the total blood flow as they are more reliable, being angle independent, easier to obtain, reflect vascular changes and might help in quick orientation about liver blood flow in pregnancies complicated by preeclampsia and HELLP syndrome.

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