Pre-eclampsia and Complexities of Measuring Uteroplacental Blood Flow

Introduction

Pre-eclampsia is a disease of pregnancy characterized by Hypertension, proteinurea and edema. It is a multisystem disorder affecting virtually every organ and system in the body. 

Various studies clearly show that the uteroplacental Blood flow, its vascular resistance, endothelial integrity, endothelial damage, the platelets and coagulation system, and neutrophils all interact in pre-eclampsia. It seems likely that unless more is known about the dynamics of uteroplacental blood flow, flow behavior and its influence on the vascular endothelium, confusion and contradiction will continue. It is therefore called, till today, the disease of theories.

Available techniques do not permit an easy or reliable quantitative estimate of the volumes of the arterial & venous components of the uteroplacental blood flow. The difficulty is because of the complex anatomical feature of the uteroplacental system. 

This article attempts to define the problems of accurate measurements of the uteroplacental blood flow. Various measurement techniques are discussed and their limitations emphasized. An overview of the various methods frequently used to measure the uteroplacental blood flow and the attendant problems associated with them are presented here. Some of the newer analytical techniques that we have developed and are in research stage are also briefly mentioned here. An article on the subject “Feto-maternal monitoring in pregnancy related vascular disorders “ was put up in Fetal monitoring and Pregnancy & Birth Section, 1999.

History 

The word eclampsia dates from the 17 Th century. It is derived from a Greek word meaning ' to shine forth ' because of the visual phenomenon accompanying the condition. The associated seizures were believed to be due to blood poisoning or toxins derived from the pregnancy, hence it was termed toxemia of pregnancy. Modern scientists attempted to explain the disease process based on observed patho-physiological changes. 

Alexander Hamilton (1781) described eclampsia as a condition associated with seizures. Bright in 1827 recognized albuminurea in addition, dropsy, relating it to renal disease and eclampsia. In 1896 when the sphygmomanometer was invented, arterial hypertension was found associated with eclampsia. Uteroplacental ischaemia and infarction reduction in maternal uteroplacental blood flow and uterine distension leading to hypertension and proteinurea through utero-renal reflex all have been implicated in pre-eclampsia (PE) (1-2). Later, with the advancement of science, the emphasis was laid more on genetic, hematological, biochemical, hormonal and immunological explanations (3-5). Brown (6), Clarified most of the pathophysiological changes associated with the disease, linking it with cortisone hormone imbalance. This hormone was implicated for all the changes. Hypoproteinaemia and vitamin deficiency has also been held responsible for this Condition (7). Recently, some studies have also related vitamins and calcium with pre-eclampsia (8-9). However, none could be proved independently until date, though association of Pre-eclampsia has been seen with changes in the levels of lipoproteins, calcium, vitamins etc. Davies and Prentice (10) suggested activation of coagulation system. The entire hematological changes are the secondary effect consequent to the primary vascular or endothelial damage. The reasons for the endothelial damage are not known (5). Petrucco (11) and others have shown a diminution in spontaneous lymphocytic transformation. Endothelin-1 gene expression is increased in placental villous tissue of Pre-eclamptics, contributing to placental vasoconstriction and vascular insufficiency (12). Chesley (13) and others have concluded that pre-eclampsia could be due to simple recessive trait. A multifactorial interaction in the aetiopathogenesis of pre-eclampsia has been proposed which takes into consideration the steroidal hormone-micronutrient interaction as the key process involved in the endothelial-trophoblastic proliferation and interactions (14).

Uteroplacental System

Anatomical and Morphological changes

The placenta is a feto-maternal organ responsible for various key functions during pregnancy. It is haemochoroidal. The increasing demand for blood flow with the advancing pregnancy is met through a complex restructuring of the uterine vasculature. The development of placental circulation i.e., fetoplacental and uteroplacental is very complex and interrelated. There are two specific tissues Systems involved in the entire development process. They are fetal syncytiotrophoblasts and the maternal decidual spiral arteries. The spiral arteries are the coiled terminal branches of arcuate artery, the intermediate chain derives its communication partially from ovarian as well as the main uterine artery. In general the system derives its communication from four arteries, two uterine and two ovarian. During pregnancy, most of the blood flowing through these terminal decidual vessels drains into the intervillous space. Structural changes: The structural changes in the spiral artery are divided into three phases. Pre-invasive, intraluminal and wall replacement. Based on placental bed biopsies, various workers have suggested uniform pathological changes, though controversy exists on this complex issue.

Normal changes: In early pregnancy, the spiral vessels tend to grow towards the lumen, and with increase in the size of the uterus, coiling is paid out and the vessels become straight with occasional right angled bends. This is followed by Pre-invasive phase where the cells lining the arteriole pile up into several layers, sometimes almost occluding the lumen. Intraluminal phase is between 16-20th week of gestation followed by wall replacement phase where the muscular elastic elements of the arteriolar wall are replaced by the fibrinoid, fibrous and amorphous tissues, in which modified myometrial cells, degenerated muscles cells and trophoblast cells are embedded.

The vascular change result in the conversion of approximate 100 to 150 spiral arteries into distended tortuous and funnel shaped uteroplacental arteries. Each vessel is approximately 2 cm in length, and communicates through multiple openings into the intervillous spaces. In the fourth, fifth and sixth months of gestation, they are frequently 500 to 1, 000 (m in diameter, but are partially obliterated by the cytotrophoblasts.

Normal Blood Flow & Rheological Behavior

The maternal arteries and veins are connected to the inter-Villous space. The spiral arteries are perpendicular and veins parallel to the uterine wall. The arterial pressure head, high towards the chorionic plate drives the maternal blood entering through the basal plate, before lateral dispersion occurs. Thus, the blood is discharged from the spiral vessels in spurts displacing the adjacent villi. The force of the spurts of blood is eventually dissipated with the creation of a small lake of blood roughly 5 mm in diameter about halfway toward the chorionic plate. The closeness of villi slows the flow of blood, providing adequate time for exchanges. After bathing the chorionic villi, the blood drains out through venous orifices in the basal plate and enters the maternal placental veins. The mean pressure at the level of the spiral artery is 70 to 80 mm. Hg. After entering the IVS the pressure rapidly diminishes from the basal plate along the length of the arterial jets. It reaches a mean value of about 10 mm. Hg in the relaxed uterus and 30-50 mm. Hg during uterine contractions. The maternal blood finally passes into the uteroplacental veins where the pressure is not more than 8 mm. Hg. In normal pregnancy, a low resistance system exists in the placenta.

Pre-eclampsia

Most current models of Pre-eclampsia are based on the assumption that the disease is one of systemic hypoperfusion with increased vascular resistance as a result of Uteroplacental insufficiency( 29 ). On the contrary, Esterling et al.(30) measured a high cardiac output preceding the development of advanced pre-eclampsia. The literature search did not reveal any maternal haemodynamic studies conducted during the early stages of pregnancy. The reduction of plasma and blood volume is generally not found in Pre-eclampsia except in conditions where it is associated with small for date or IUGR (intra-uterine growth restriction) babies (31). An intensive management of severe PE or Eclamptic patient may help in reducing the severity and the mortality and morbidity associated with the condition (32, 33). The haematocrit in severe Pre-eclampsia is increased, whereas in normal pregnancy, it falls from 0.40-0.47 to a minimum of 0.31-0.34. Endothelium: Endothelial cells play a very important role in maintaining the integrity of the vascular compartment. It mediates immune and inflammatory responses and modifies the contractile response of the underlying smooth muscle cell by vasodilators like EDRF (endothelial derived relaxing factor) and prostacyclins. Pre-eclampsia has been directly linked with endothelial dysfunction, low EDRF, prostaglandins and high endothelins. Inhibition of EDRF by free haemoglobin has been hypothesized (35).

Uteroplacental Blood Flow Measurement Techniques

Over the years, a number of methods have been developed but none have been standardized in view of the difficulty in precise measurement. The various methods include endocrine clearance rate, thermistor method, ultrasonic flowmetry, radioisotopic markers, and electromagnetic flowmeter. More recently, Doppler velocimetry, a non-invasive method has been introduced. Doppler measurements and its analysis are in early stages of development.

Endocrine Clearance Rate

A reduction in the metabolic clearance of dehydroisoandrosterone sulphate in pre-eclampsia has been demonstrated (36). This reduction preceded clinically detected disease. However, proper degree of correlation between clearance and flow was not possible. Senner et al. (37) measured the flow with the C19 steroid clearance rate. Brown and Vealle (1) investigated the maternal blood flow using Na 24-clearance rate. The results are highly variable.

Electromagnetic Flow Meters

Assali et al.38 ) performed direct measurement of uterine blood flow using this technique, however, they could not use it for routine investigation owing to the wide variability in results.

Thermistor Method

This invasive method has been used to measure uterine blood flow in the non-pregnant condition. Its role in pregnancy is yet to be ascertained. Randall et al. (39) tried to validate thermal techniques for measuring pelvic organ blood flow. The temperature changes in both the uterus and the vagina correlated well with the blood flow changes measured by transit-time ultrasonic and microsphere method. Thermal clearance did not correlate well with the blood flow in the vagina or uterus. The poor correlation is due to the fact that it measures flow in the vicinity of the probe. The pressure from the probe may cause a change in local tissue perfusion. The thermal conductance is also subject to differences in probe geometry, sensitivity, construction, and type and nature of the tissue it is placed against. Local changes may occur with posture. This method may not be acceptable in pregnancy, because it is invasive, and results show wide variation and thus can not be standardized.

Radiosotope method

This method measures the rate of disappearance of radioisotopes from the choriodecidual space. It measures the extent of placental perfusion. Recently, radio-isotopic labeled microspheres have been used to quantify the blood flow (39,40). Some of them have con-firmed a reduction in the intervillous blood flow in pre-eclampsia, although the results are varying. The limitations of these methods are its invasive nature, variability of results and the potential biohazards of the radioinucleotide used in the technique. 

Dynamic placental scintigraphy

This is a useful method to measure the total blood flow to uterus. It fails to document the specific vascular changes. The metastable radionuclide indium 113m is used, which after decay binds to transferrin and is trapped in the placenta. The radioactivity is counted using a scintillating camera and plotted as time activity curve. The quotient of maximum activity divided by the rise time gives the placental blood flow (41). Its results are comparable to the microsphere technique. 

Doppler velocimetry

This method is now widely used to measure the uteroplacental and umbilical or fetal organic blood flow to understand various underlying pathology. This is relatively safe, noninvasive, reasonably accurate, particularly after the introduction of color Doppler flow mapping. Campbell (42) introduced Doppler method to study the uterine circulation. The most common measurements are S/D ratio, resistance index and Pulsatility index. All these indices, using velocity or frequency values, are ratios and are therefore independent of the angle of incidence as well as the emitting frequency. The S/D ratio is the simplest index to calculate. It is calculated by dividing the maximal systolic Doppler shift by the end-diastolic shift. Resistance index (RI) is calculated from the difference in systolic and diastolic shifts divided by the systolic value [(S/D)/S]. Pulsatility index is the most commonly used index for the evaluation of downward or upward circulatory obstructions. The times averaged mean velocity calculates it over an entire number of cardiac cycles. However, it requires a digitized waveform [(S/D)/mean]. The indices are highly reproducible, comparable and correlate with the changes in the physiological parameters. This method has since been used both for screening and determination of the extent of pathology. The studies have shown a characteristic low resistance or pulsatile waveform in normal pregnancy. High pulsatile velocity waveform or high S/D ratio, RI and PI indicate increased downward impedance to flow. The mechanism whereby these abnormal waveforms occur is uncertain, although it may relate to increased downstream resistance within the placental vascular tree. The resistance can be caused by the obliteration of spiral vessel, the tertiary stem villus arterioles, local constrictions, or prolonged vasoconstriction. The low prevalence of perinatal deaths and other serious perinatal outcome variable results in a low positive predictive value for Doppler velocimetry when used as a screening test in low-risk population’s (43). However, at present its role along with other biophysical and clinical support may justify its applicability in high-risk pregnancy (44). 

Limitations of the Doppler technique

Quantitative measurement of blood flow in the microcirculation is an important factor in analyzing the interactions between the flow dynamics and vascular structures in health and disease. 

It is not yet possible to quantify the pressure gradient or flow volume with Doppler technique in the uteroplacental microvessels. The pressure gradient can be derived from velocity waveforms using Bernoulli’s equation. For flow measurement accuracy with which the velocity distribution in the vessel is averaged is important (45). But in pregnancy the intricately ramifying spiral vessels can not be mapped easily so specific waveforms can not be derived to quantify the pressure or the flow volume. Future research should be directed towards advancement in image velocimetry technique. The predictive value of Doppler in Pre-eclampsia is low because of false positive result. This may be due to lack of refinement of the technique and inadequate modeling. At present most of the recordings are obtained from either arcuate or uterine artery. The arcuate artery obtains collaterals from both the ovarian as well as uterine artery of both sides; hence four arteries are involved. Doppler recordings from one artery fail to demonstrate the abnormality of the blood flow in the other arteries.

Further advances in Doppler technique are a pre-requisite for the realization of its potential as an investigative tool in understanding the haemodynamic changes in pregnancy. This is of special interest to our interdisciplinary research team.

Use of Interdisciplinary Science & Models in Pre-eclampsia

Animal Models

Various animal models have been used. However, the acuteness of the condition could not be replicated. The absence of an ideal animal model has been one of the major hurdles, responsible for the incomplete understanding of the disease process. Young (1912) and Goldblatt (1939) proposed the concept of chronic placental ischaemia responsible for toxemia. Most of the workers since then have tried to create a Pre-eclampsia like condition by the complete or partial occlusion of descending aorta, renal artery, and internal iliac or uterine artery. They concluded that interference with the blood supply of the pregnant uterus might be an important factor in the pathogenesis of Toxemia of pregnancy. 

Cavanagh et al. (46) produced Pregnancy induced hypertension in a pregnant baboon by interfering with the Uteroplacental circulation. Animals in the experimental group developed hypertension and showed reduced Plasma renin activity. Fetuses delivered to them were of low birth weight as compared to those in the control group; a similar trend was observed in respect of placental weight and amniotic fluid volume. Theobold (47) created a total occlusion of the aortic bifurcation by an embolus. But there was no sign or symptoms of Pre-eclampsia and the babies born to them were normal. This suggests that it is the magnitude of collateral uteroplacental circulation, which may contribute to the genesis of this condition. Similar human studies are not possible because of ethical problems involved. 

Guillermo et al. (48) observed the cardiovascular changes after closure of uterine circulation during pregnancy. He concluded that the uterine circulation influences the systemic cardiovascular system through long and short-term loop by producing hormones with a vasoactive effect. A long-term effect mediated by estradiol, produced by the fetoplacental unit, produces significant alterations of the systemic vascular system in the mother and increases uterine blood flow. A faster response system, which responds to decreases in the uterine circulation by a release of a stronger vasoconstrictor of the systemic circulation, would increase systemic vascular resistance; therefore, systemic arterial pressure increases. This in turn will restore uterine circulation. The nature of the latter system may be one of the processes involved in Pre-eclampsia due to inadequate trophoblastic invasion and failure of the conversion of spiral vessels into uteroplacental vessels as proposed by Brosen.

Mathematical Model 

The consensus of opinion is that the changes in the haemodynamic of the uteroplacental system during placentation are localized at the level of terminal spiral vessels. As such, it is very difficult to measure the pressure-velocity profile from the affected site of pathophysiology. Mathematical modeling of the physiological fluid flow may provide a better understanding of the underlying pathophysiology. Surprisingly, there are no reports in the literature, which attempts this approach in understanding the flow behavior of the uteroplacental system. The mathematical model is capable of incorporating as many variables as occur in the real system. In this context, the role of oscillatory flow on the endothelial proliferation and function may form the basis of future work in the field of clinical hemorheology (49,50).

Electrical Analog: The electrical transmission line analogy for impedance for a network (branching) to understand the flow has been used by Noordergraaf (51), who used Poisselleos value for a steady flow. In nonlinear systems, resistance is very high; therefore all the haemodynamic equation cannot be embodied in electrical analog. The resistive component of vascular impedance is frequency dependent, which is not the case in electrical resistors; however impedance in inductances can be frequency dependent. A more representative non-linear electrical model in necessary to simulate the flow study in human being. Mo et al. (52) have tried to work on an equivalent electrical analog model to understand the Doppler velocity wave forms obtained from the uterine artery by computer simulation. Their model was inadequate to explain the pathophysiological changes. They have used a linearized Navier-stokes equation and reduced it to a first order differential equation taking into consideration a single distensible axisymetric circular tube with a nonviscous elastic vessel wall. Therefore it could not adequately explain all the changes taking place at the level of complex spiral or uteroplacental vessel (53). We have further improved upon the electrical model and have been able to incorporate non-linearities by using the junction field effect transistor. This model and the frequency analysis could predict the vascular changes at the level of proximal uterine or arcuate artery in response to different dynamic process involved in the uteroplacental vessels (54,55,56).

Conclusion

The trigger, which initiates PRE-ECLAMPSIA, is not yet known. It is therefore necessary to understand the mechanism of blood flow in the uteroplacental system. Available biomedical investigative techniques could not provide the much-needed answer to the problem because of the complex anatomy of the uteroplacental system. It is technically difficult to measure the blood flow from all the four ovarian and uterine arteries simultaneously. Secondly, it is also very difficult to measure blood flow in the highly complex venous plexus draining the blood. Therefore accurate measurement of A-V difference is practically impossible. Measurements were generally obtained using different invasive techniques in the women prior to elective termination of pregnancy. An attempt is made here to review the current status of pre-eclampsia and define the problems of studying the uteroplacental haemodynamic changes and at the same time suggested some alternate approach for future research.

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See also

Feto-Maternal Monitoring in Pregnancy Related Vascular Disorders by Dr. Amit Sengupta, MBBS, MD, Ph.D., OBGYN.net Editorial Advisor Consultant in Obs. & Gyne. and Biomedical Eng. Scientist, New Delhi, India