OBGYN.net: The Universe of Women's Health

Preclampsia y la dificultad de medir el flujo uteroplacentario - El intento de una mirada profunda

Traducción: Dra. Marisa Geller

Introducción

La preclampsia es una patología del embarazo caracterizada por hipertensión, proteinuria y edema. Es una enfermedad multisistémica que afecta a todos los órganos y sistemas del cuerpo.

Varios estudios muestran que el flujo uteroplacentario, la resistencia vascular, la integridad y el daño endotelial, las plaquetas, el sistema de coagulación y los neutrófilos interactúan en la preclampsia. Parecería que, salvo que se sepa más sobre la dinámica del flujo uteroplacentario, su comportamiento y su influencia en el endotelio vascular, continuará habiendo confusión y contradicción en este tema. Es por eso que hoy en día se la llama la enfermedad de las teorías.

Las técnicas disponibles no permiten estimar cuantitativamente los volúmenes de los componentes arterial y venoso del flujo uteroplacentario. La dificultad está dada por la complejidad anatómica del sistema uteroplacentario.

Este artículo intenta definir los problemas de una medición precisa del flujo uteroplacentario. Se describen distintas técnicas y sus limitaciones. Se muestran los distintos métodos para medir el flujo uteroplacentario y los problemas que se suscitan con cada uno de ellos

Historia 

La palabra eclampsia data del siglo XVII. Deriva de la palabra en griego que significa 'brillar' por el fenómeno visual que acompaña a esta condición. Las convulsiones que se asocian a esta patología, se creía que se debían al envenenamiento de la sangre o a toxinas que derivan del embarazo, por lo que se llamó toxemia del embarazo. Luego se intentó explicar esta patología basados en observaciones de los cambios fisiopatológicos.

Alexander Hamilton (1781) describió a la eclampsia como una condición asociada a las convulsiones. Bright en 1827 reconoció la albuminuria y la acumulación de líquidos y relacionó a la eclampsia con una falla renal. En 1896 cuando se inventó el esfingomanómetro, se asoció a la hipertensión arterial con la eclampsia. La isquemia y el infarto uteroplacentario reducen el flujo y llevan a la distensión uterina lo que trae aparejado hipertensión y proteinuria por reflejo utero-renal (1-2). Luego, con el avance de la ciencia, se encontró una explicación basada en lo genético, hematológico, bioquímico, hormonal e immunológico (3-5). Brown (6), relacionó esta patología con un disbalance del cortisol, hormona implicada en todos los cambios. También se responsabilizó a la hipoproteinemia y al déficit de vitaminas (7). Recientemente, algunos estudios relacionaron a las vitaminas y al calcio con la preclampsia (8-9). Ninguno mostró una asociación independiente con la preclampsia, sin embargo se observó una asociación con los cambios en los niveles de lipoproteínas, calcio, vitaminas etc. Davies y Prentice (10) sugirieron una activación del sistema de coagulación. Los cambios hematológicos son efectos secundarios del daño del endotelio vascular. Las causas de la injuria endotelial no son conocidos (5). Petrucco (11) y otros mostraron una disminución espontánea de la transformación linfocítica. La expresión del gen de endotelina-1 está aumentado en las vellosidades placentarias en la preclampsia, contribuyendo a la vasoconstricción y a la insuficiencia vascular (12). Chesley (13) y otros concluyeron que la preclampsia podría ser un rasgo recesivo. Se ha propuesto una etiopatogenia multifactorial en la preclampsia que toma en consideración la nutrición de la hormona esteroidea como clave en el proceso involucrado en la proliferación del endotelio trofoblástico (14).

Sistema Uteroplacentario

Cambios Anatómicos y Morfológicos

La placenta es un órgano feto-materno responsable de varias funciones claves durante el embarazo. Es hemocorial. El aumento de la demanda de flujo con el avance del embarazo se debe a la reestructuración de la vascularización uterina. El desarrollo de la circulación placentaria, es decir, la fetoplacentaria y la uteroplacentaria es muy complejo y se interrelaciona. Hay dos tejidos específicos involucrados. Son el sinciciotrofoblasto fetal y las arterias espiraladas de la decidua materna. Las arterias espiraladas son las ramas terminales de las arterias arcuatas, la cadena intermedia deriva su comunicación parcialmente del ovario y de la arteria uterina. En general el sistema deriva su comunicación de cuatro arterias, dos uterinas y dos ováricas. Durante el embarazo, la mayoría de la sangre que fluye por estos vasos deciduales terminales drenan al espacio intervelloso.

Cambios estructurales: Los cambios estructurales en la arteria espiralada se dividen en tres fases: preinvasiva, intraluminal y de reemplazo de la pared. Basados en biopsias placentarias, se sugirieron cambios patológicos uniformes, a pesar de haber controversia en este aspecto.

Cambios normales: Al principio del embarazo, los vasos espiralados van creciendo hacia la luz, y con el crecimiento del útero, los vasos se hacen rectos con algunas torsiones en ángulo recto. Esto es seguido por una fase preinvasiva donde las células de las arteriolas se apilan en varias capas a veces ocluyendo la luz. La fase intraluminal se da a las 16-20 semanas seguida por un reemplazo de pared donde la capa elástica muscular de las arteriolas es reemplazada por tejido amorfo, fibroso y fibrinoide.

Estos cambios vasculares producen una conversión de aproximadamente 100 a 150 arterias espiraladas en arterias uteroplacentarias tortuosas y con mayor distensión. Cada vaso tiene aproximadamente 2 cm de longitud y se comunica con los espacios intervellosos. En el cuarto, quinto y sexto mes de embarazo, son 500 a 1, 000 metros de diámetro, pero están parcialmente obliterados por citotrofoblasto.

Flujo Sanguíneo Normal & Comportamiento Rheologico

Pre-eclampsia

Los modelos de preclampsia están basados en la hipoperfusión con aumento de la resistencia como resultado de una insuficiencia uteroplacentaria (29). Esterling y colaboradores (30) encontraron un aumento del gasto cardíaco previo al desarrollo de una preclampsia avanzada. La búsqueda de literatura no mostró estudios de hemodinamia materna realizados en la primera etapa de la gestación. Generalmente no se encuentra una reducción del volumen plasmático en la preclampsia salvo en condiciones donde se asocia con RCIU (retardo de crecimiento intrauterino) (31). Un manejo intensivo de la preclampsia severa o la eclampsia puede ayudar a reducir la morbimortalidad asociada con esta condición (32, 33). El hematocrito en estas pacientes aumenta, mientras que en un embarazo normal, baja de 0.40-0.47 a un mínimo de 0.31-0.34.

Técnicas para la medición del flujo uteroplacentario

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. 

References:

1. Brown JC and Vaelle N. The maternal placental blood flow in normotensive women. J Obstet Gynaecol Br Commonwealth 1953;60:141.

2. Berger M and Cavanaugh D. Toxaemia of pregnancy & the hypertensive effect of acute experimental placental ischaemia. Am J 
Obstet Gynecol 1963; 87:293.

3. World Health Organization study group. The hypertensive disorders of pregnancy.W.H.O. Technical report series 758, Geneva: WHO, 1987. 

4. Davey DA. Hypertensive disorder in pregnancy. In: Whitfield CR, ed. Dewhurst Obs Gynae for Post graduates. Oxford: Blackwell Scientific, 1986, pp 200-241. 

5. Lyall F and Greer IA. Is pre-eclampsia a preventable disease? In : Bonner J, ed. Recent advances in Obstetrics and Gynecology,18.UK:Churchill Livingston, 1994, pp 3-21.

6. Brown FJ. Etiology of Pre-eclampsia & Eclampsia. Lancet (ii) 1958;2:115.

7. Chowdhuri, SK. Relationship of PEM & PET. Am J Obstet Gynecol 1970; 107:33.

8. Ramos SL, Godelvalle D, Briones PN, C Walker RN, I delke F gandler. Prevention of PE by calcium suppl.in Ang. sensitive patients. SPO Abstracts, Am J Obstet Gynecol 1994; Jan: 408.

9. Belizan S. Calcium suppliment to prevent Pre-eclampsia. New England J Med 1991; 325:1399.

10. Davies JA, Prentice CRM. Coagulation changes in PIH & growth retardation. In : Greer IA, Turpie AGG, Forbes CD. eds. Haemostesis & thrombosis in Obsterics and Gynecology.London : Chapman & Hall, 1992, pp 143-162.

11. Petrucco OM, Thomson NM, Lawrance JR, Welder MW. Immunofluorescent studies in renal biopsy in pre-eclampsia. Br Med J 1974;1:473.

12. Mc Mahan LP, Redman CWG, Expression of the three endothelial genes & plasma levels of ET in PE & normal gestation. Clin Science 1993; 85(4):417.

13. Chesley LC, Cosgrove RA, Annitto JE. A follow up study of eclamptic women. IV th periodic report. Am J Obstet Gynecol 1962; 83:1360.

14. Sengupta A and Guha SK. The multifactorial interactions in the Aetiopathogenesis of EPH-gestosis-A hypothesis. Medical Hypothesis 1994; 43 ( 5 ): 322.

15. Brosen IA, Robertson WB, Dixon HG. The physiological response of the vessel of the placental bed to normal pregnancy. J pathol Bacteriol 1967; 93:569.

16. Brosen I, Dixon HG, Robertson WB. Fetal growth retardation and the arteries of the placental bed. Br J Obstet Gynaecol 1977; 84:656.

17. Brosen IA. Morphological changes in the Uteroplacental bed. Clin in Obstet Gynecol 1977; 4:573.

18. Robertson WB. The pathological response to the vessels of the placental bed to hypertensive pregnancy. J pathol Bacter 1967; 93:581.

19. Ramsey EM, Cornor GW, Donnar MW. Serial & Cineradioangiographic visualization of maternal circulation in primate placenta. Am J Obstet Gynecol 1963; 86:213.

20. Dixon HG, Browne JCM, Davey DA. Choriodecidual & myometrial blood flow. Lancet 1963; 2: 369.

21. Sibai BM, Shanklin M.Ultrastructural aspects of PE-Placental bed & uterine boundary vessels. Am J Obstet Gynecol 1989; 161:735.

22. Pijnenborg R, Anthony J, Davay DA, et al. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet gynecol 1991; 98:648.

23. Meekins JW, Pijnenborg R, Hanssens M, McFayden IR, Asshe Av. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclampsic pregnancies. Br J Obstet gynecol 1994; 10: 669.

24. Eskey T, Stolte l, Seelan l, Lamping P. Radioangiographicstudies of the maternal circulation in the human placenta. Arch Gynaek 1965; 200:735.

25. Burwell CS, Strayhorn WD, Flicinger D, et al. Circulation during pregnancy. Arch Intrn Med 1938; 11:979.

26.Gerretsen G, Huisjer HJ, Elema JD. Morphological changes of the SA in the Placental bed in relation to PE & IUGR. Br J Obstet Gynecol 1981; 88:876.

27. Macdonald RR. In : The Scientific basis of obstetrics and gynaecology 2. UK : Churchill livingston press, 1978, pp 188-196.

28. Harold Fox. Development and structure of the placenta and fetal membrane. In: Philipp E, Sctchell M, Ginsburg J, eds. Scientific foundation of Obstetrics and Gynaecology 4. Oxford: Butterworth-Heinmann, 1991, PP.287-298.

29. Wisser W. Central haemodynamic observation in untreated PE patients. Hypertension 1991;17:1072.

30. Easterling TR, Beneditti TJ, Schmuker BC, Millard SP. Maternal haemodynamics in normal & pre-eclamptic pregnancies-A longitudinal study. Obstet Gynecol 1990; 76:1061. 

31. Sibai BM, Anderson GD, Spinnato JA, Shaver DC. Plasma volume findings in patients with mild PIH. Am J Obstet Gynecol 1983; 146:756.

32. Richards AM, Moodley J, Graham DI, Bullock RR. Active management of the unconscious eclamptic patient. Br J Obstet Gynaecol 1986; 93:554.

33.Sengupta A, Muralidharan S, Bhattacharya A, Gode AG. Intensive management of eclamptic patients-an overview. In : Ripmann ET, Dasgupta S, Parvez H, eds. Proc. of XIX international Congress of Pathophysiology of Pregnancy ( Org. Gestosis-Basel ), Rome: CIC, 1992. 

34.Cuningham FG, McDonald PC, Leveno KJ, Gant NF, Gilstrap LC. In : Williams Obstetrics 19. USA : Printice-Hall, 1993, pp 763-813

35. Sarrel PM, Lindsay DC, Poole-wilson PA, et al. Hypothesis-Inhibition of endothelium - derived relaxing factor by hemoglobin in the pathogenesis of pre-eclampsia. Lancet 1990;336:1030.

36.Gant NF, Hutchinson HT, Siiteri PK, MacDonald PC. Study of the metabolic clearance of DHAS in pregnancy. Am J Obstet Gynecol 1971; 111:555.

37. Senner JW, Stanczyk FZ, Fritz MA, Novy MJ. Relationship of uteroplacental blood flow to placental clearance of maternal plasma C-19 steroid: Evaluation of the mathematical model. Am J Obstet Gynecol 1985; 153:573.

38. Assali NS, Rauramo L, Peltonen T. Measurement of uterine blood flow & uterine metabolism. Am J Obstet Gynecol 1960; 79:86.

39. Randall NJ, Beard RW, Sutherland IA, Figueroa JP, Drost CJ, Nanthaniolsz PW. Validation of thermal techniques for measurement of pelvic organ blood flow in the pregnant sheep. Am J Obstet Gynecol 1988; 158: 651.

40. Johnson RL, Gilbert M, Giacomo M, Battalgia FC. CO distribution and uteroplacental blood flow in the pregnant Rabbit: A comparative study. Am J Obstet Gynecol 1985; 151 ( 5 ):682.

41.Lunell NO, Nylund L. Uteroplacental blood flow. Clinical Obstet Gynecol 1992; 35 (1):108.

42. Campbell S, Diaz-Recasens J, Griffin DR et al. New Doppler technique for assessing uteroplacental blood flow. Lancet (ii) 1983; 1:675.

43. Brown MA, North L, Hargood J. Uteroplacental Doppler ultrasound in routine antenatal care. Aust NZ J Obstet Gynecol 1990;30:303.

44.Sengupta A, Guha SK, Anand S, Jayaraman G, Biswas P, Rehana HMK. Can conventional biomedical investigative techniques unfold the mysteries of uteroplacental system in pregnancy? A critical study. In : The proceedings of RC-IEEE-EMBS,USA. New Delhi:CBME-IIT/AIIMS, 1995, pp 1.83-1.84.

45. Singh M, Umrani J, Prakash B,Namasivayan A. blood flow analysis in mesentric arterial bifurcation by axial tomographic and image velocimetry techniques. In: Singh M, Saxena VP, eds. Advances in physiological fluid dynamics. India: Narosa Publication house, 1996,pp 109-115.

46. Cavanaugh D, Rao PS, et.al.Pregnancy induced hypertension. Am J Obstet Gynecol 1985; 151 ( 7 ):990.

47. Theobold GW. In: Placental hypothesis in pregnancy toxaemia, London: Henry Kimpton, 1955,PP 319-347.

48. Guillermo JV, Sunshine K. and Hugo FR. Cardiovascular changes after closure of uterine circulation during pregnancy. Am J Physiology 1990; 258 ( Reg. Int. Comp. Pysiol.27 ) : R1431.

49. Copley AL, Silbergerg A. On the scope of the science of biorheology and aims of biorheology. Biorheology 1986;23:307.

50. Sengupta A, Biswas P, Jayaraman G, Guha SK. Understanding uteroplacental blood flow in normal and hypertensive pregnancy through a mathematical model.Med Biol Eng Com 1997,35:223.

51. Noordergraff A.In: Haemodynamics. In: schwann H, Bioengineering, N.york:Mcgraw Hill,1969.

52. Larry YL Mo, Bascom PAJ, Ritchie K, McCowen LME. A transmission line modeling approach to the interpretation of uterine Doppler waveform. Ultrasound Med Biol 1988; 14(5): 365.

53.Adamson SL, Morrow RJ, Bascom PAJ, Mo LYL, Ritchie JKW. Effect of placental resistance, arterial diameter & blood pressure on the uterine artery waveform-a computer modeling approach. Ultrasound Med Biol 1989; 15:437.

54.Sengupta A. A biotechnological study of the pathophysiology of the uteroplacental vascular system in pregnancy and its related complications of pre-eclampsia. Ph.D. thesis in biomedical Engineering, Indian Institute of Technology, Delhi, 1995.

55.Sengupta A. An experimental study to evaluate the technological limitations in the understanding of the haemodynamic change in pre-eclampsia. Blood Pressure Monitoring, USA 1998,3(4): 241-246. 

56. Aman Gayasen and Sunil Kumar: MOSFET Based modeling of microvascular system, B.Tech Project, Electrical Engineering 2001; Indian Institute of Technology, Delhi, India;(Guide: Dr. Amit Sengupta and Prof.D. Nagchowdhury).

Ver también