Fetal Cardiovascular System Research Articles

Fetal heart rate following coelocentesis.

For psychological reasons, coelocentesis was performed in 20 women prior to termination of pregnancy, at 6-11 weeks of gestation. The fetal heart rate (FHR) was measured immediately before the procedure and at 1, 5, and 10 min afterward. There was no significant difference between FHR before coelocentesis compared to the values at 1 min (mean = 158, range 114-178; z = -0.629, P = 0.529), 5 min (mean = 160, range 121-179; z = -0.191, P = 0.848), or 10 min (mean 159, range 117-183; z = -0.214, P = 0.83) after the procedure. These findings suggest that coelocentesis does not have a major effect on the fetal cardiovascular system.

Mathematical modelling of the human foetal cardiovascular system based on Doppler ultrasound data

A lumped parameter model of the human foetal circulation primarily based on blood velocity data derived from the Doppler analysis was developed in this study. It consists of two major parts, the heart and the foetal vascular circulation. The heart model accounts for both ventricular and atrial contractility. The circulation was divided into 19 compliant vascular compartments in order to describe all of the clinically monitored sites. The model parameters refer to the final gestation period and were derived either from literature on foetal sheep circulation or from anatomical dimension monitoring of the human foetus. No control mechanism is incorporated into the model. The model was validated by comparing several index values of simulated velocity curves to those of the experimental Doppler waveforms. The mean and maximum percentual errors in the estimation of the experimental results by the model are 7.7% and 20.1%, respectively. Velocity and pressure tracings of the foetal circulation were investigated, as well as regional blood flow rate distribution.

Can twin fetuses be numerically clustered characterizing fetal cardiovascular system function?

To clarify whether twin fetuses could be clustered quantitatively observing in utero cardiovascular system function, 71 twin-paired fetuses between 24 and 40 weeks' gestation were subjected. Cluster analysis was performed using four variables; end-diastolic dimension and fractional shortening in the right ventricle (EDD, FS), resistance index in the umbilical artery (RIUA) and urine production rate (UPR). Three different groups were revealed. In Cluster 1 (C1), larger fetuses showed a significant increase in both EDD and UPR, and a significant decrease in FS, while smaller fetuses had a significant increase in RIUA and a decrease in UPR. In Cluster 2 (C2), smaller fetuses showed a significant increase in RIUA. Cluster 3 (C3) showed no significant deviations in any variable when referring to singleton pregnancies. C1 had a higher perinatal mortality rate than either C2 or C3, with the cause of death being cardiac failure in larger fetuses and renal failure in smaller fetuses. The frequencies of discordancy, hemoglobin difference above 5 g/dl and monochorionic placenta in C1 were also higher than fetuses in C3. C2 also showed higher frequencies of discordancy and small-for-gestational age than C3 fetuses. In C2 and C3, respiratory insufficiency was found to be the cause of neonatal death. The results revealed that C1 consists of twins with both larger and smaller fetuses displaying cardiac failure with an increase in renal perfusion and a decrease in renal and placental perfusion, respectively, and C2 consists of twins with smaller fetuses having both placental insufficiency and intrauterine growth retardation. C3 consists of twins with both lager and smaller fetuses having normal circulation, when compared to singleton pregnancy.

POWER SPECTRAL ANALYSIS OF UMBILICAL ARTERY FLOW VELOCITY IN WEEK 10 TO 12 HUMAN FETUS. † 138

The fetal cardiovascular system is precisely regulated during development. We used power spectral analysis to define heart rate and peak velocity amplitude variability in the human fetus during conditions of maternal spontaneous and stop breathing. Recordings were made from the floating loop of the umbilical artery using a Toshiba SHH140A pulsed-Doppler velocimeter with a 6 MHz transvaginal probe. Ten velocity time series were recorded during spontaneous breathing from 8 fetus at week 10 (n=2), 11(n=3) and 12(n=3). Ten non-matched velocity time series were recorded during stop breathing from 8 fetus at week 10 (n=5), 11(n=1), and 12(n=2). Ultrasound spatial peak temporal average was less than 100m W/cm2. Velocimeter wall filters were 70 or 100 Hz. Doppler forward flow audio signals were recorded at 44KHz for > 16 seconds. Peak velocity, mean velocity and instantaneous heart rate were determined for each time series. Mean heart rate and mean velocity were determined for each velocity time series. Peak velocity and heart rate variability time series were de-trended via low-order polynomial fit to remove DC-drift, and power spectra analyzed using FFT. To compensate for mean heart rate differences between fetus, we normalized spectral frequency axes for each fetus by heart rate. This unitless frequency axis ranged from zero (DC) to 1(heart rate). To compensate for mean-velocity (or mean heart rate) differences, we computed the ratio of spectral power in 10 pre-set bands (0.1 increments of normalized frequency) to total spectral power. The average power ratios for heart rate variability during stop breathing were 3%, 15%, 27%, 26%, 16%, 8%, 3%, <1%, <1%, and <1% respectively, in each band. During spontaneous maternal breathing, these ratios shifted 4%, 16%, 21%, 22%, 22%, 10%, 2%, <1%, <1%, and <1%, respectively. The average power ratios for peak-velocity variability during stop breathing were 27%, 26%, 19%, 15%, 7%, 3%, 1%, <1%, <1%, and <1%, respectively. During spontaneous maternal breathing these ratios shifted to 23%, 40%, 14%, 10%, 6%, 3%, 1%,,<1%, <1%, and <1%, respectively. These are new tools for analysis of the homeostasis in the early human fetus. We speculate that cardiovascular alteration associated with maternal fetal pathology changes these measures and may lead to earlier clinical diagnosis and therapy.

Cardiovascular physiology of the human fetus

Efforts to develop a system for the diagnosis and treatment of heart disease in the fetus and neonate are dependent upon a fundamental understanding of the interaction between form and function of the fetal cardiovascular system. Recent advances in the field of molecular biology have suggested that single gene defects may be involved in the development of a larger proportion of congenital heart disease than was previously appreciated. Once organogenesis has been completed the architecture of the fetal cardiovascular system reflects the pressure and volume of blood flow through the developing chambers and blood vessels. Fundamental differences in cellular structure and arrangement of the myocardium and functional changes attending biochemical differences in contractile elements and their interaction with available cations impart alterations on mechanical function of the intact heart, and alter the response of the myocardium to alterations in structure and stress. In this review of cardiovascular physiology of the human fetus we attempt to review observations of regional blood flow distribution in the normal and abnormal fetal circulation. We rely upon two-dimensional echocardiographic imaging of cardiovascular structure and Doppler analysis of flow in the human fetus to draw conclusions regarding the normal and abnormal physiology and compare these findings to the fetal cardiovascular principles that have been previously defined in the lamb.

Effects of losartan on the cardiovascular system, renal haemodynamics and function and lung liquid flow in fetal sheep.

1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P <0.01) and diastolic (P <0.01) pressor response to 5 microg angiotensin II (AngII) i.v. from 27.4 +/- 1.5 to 7.4+/-0.9 and from 17.5 +/- 1.3 to 5.4 +/- 0.6 mmHg, respectively, after 1 h and to 6.1 +/- 0.5 and 4.4 +/- 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 microg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P <0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P <0.05), fetal PO2 decreased (P <0.01), PCO2 did not change and pH decreased (P <0.01), as did plasma bicarbonate levels (P <0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P <0.01) and an increase in blood flow (P <0.05). Glomerular filtration rate decreased (P <0.05); thus, filtration fraction decreased (P <0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P <0.01) and became negative. Urine flow decreased (P <0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P <0.05). There was a decrease in lung liquid flow (P <0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.

Nutrition and fetal growth

Nutrient supply to the fetus is a key factor in the regulation of fetal growth. However, the direct supply of nutrients to provide building blocks for tissue growth is likely to be only a minor component of this regulation. The indirect effects of nutrition on fetal endocrine and metabolic status, and on the interaction between the fetus, placenta and mother all of which must be coordinated to allow fetal growth are also important. Maternal undernutrition may alter the growth of the fetus and its different component tissues in a way which cannot be explained solely on the basis of reduced substrate supply during the rapid growth phase of the tissues involved. Adaptation to altered substrate supply, during both undernutrition and refeeding, involves sequential changes in the metabolic and endocrine interactions between the fetus and the placenta. In addition, undernutrition has long-term consequences for the fetus. There is evidence for nutritional programming of fetal endocrine and cardiovascular systems before birth. Nutritional effects may also persist over more than one generation. The effects of nutrition on fetal growth are far more complex than simply those of substrate deprivation.

Smoking, pregnancy and the fetus.

Smoking may influence a women's reproductive ability by having adverse effects on fertility, the early embryo and the fetus. The ability to become pregnant and to maintain the pregnancy long enough for it to be clinically detected is reduced in smokers. Smoking can adversely influence several of the crucial steps within the reproductive process required for achieving a pregnancy. Despite the increased miscarriage rate in women that smoke there is no evidence to suggest that smoking can cause fetal abnormalities. The chemical composition of cigarette smoke is more closely related to reduction in fetal growth than the number of cigarettes smoked. In smokers, the placenta appears remarkably normal. The effects of smoking could be due to one or more of the hundreds of different chemical substances in tobacco smoke, but apart from carbon monoxide and nicotine, little is known about the effects of other toxins. Nicotine can adversely affect uterine and placental blood flow by causing constriction of the blood vessels. It can also affect both the maternal and fetal blood pressure and heart rate, but its action on the fetal cardiovascular system does not appear to be dependent on its effect on placental perfusion.

Acute maternal and fetal cardiovascular effects of caffeine ingestion.

Little data exist regarding the acute maternal and fetal cardiovascular effects of caffeine ingestion. The purpose of this study is assess the cardiovascular effects of caffeine ingestion in pregnant subjects and their fetuses. We examined seven caffeine-naive gravidas longitudinally at 25.7 (SE +/- 0.7) and 36.1 (+/- 0.7) weeks' gestation, before and after ingestion of a caffeine citrate solution (100 mg/m-2 body surface area). Maternal pulse, blood pressure, fetal heart rate, and fetal heart rate accelerations were determined before and after caffeine ingestion. Uterine artery, fetal aorta, and umbilical artery flow velocity waveforms were examined at similar intervals. Significant before and after caffeine differences, regardless of gestational age, were noted for maternal pulse (85.1 vs 74.2 beats/min), diastolic blood pressure (65.9 vs 73.8 torr), mean arterial blood pressure (81.5 vs 87.5 torr), uterine artery systolic-to-diastolic (S/D) ratio (1.9 vs 2.4), fetal heart rate (144.6 vs 135.4 beats/min), and fetal heart rate accelerations (1.6 vs 4.2 per 30 minutes). Differences for fetal aortic and umbilical artery S/D ratios were not significant with respect to caffeine administration. Fetal aortic peak velocities increased with caffeine (85.5 vs 130.2 cm/sec) and the increase was augmented with advancing gestational age. We conclude that maternal ingestion of modest amounts of caffeine citrate in caffeine-naive subjects significantly affects both the fetal and maternal cardiovascular systems.

Effects of maternal ingestion of low-dose aspirin on the fetal cardiovascular system

OBJECTIVE: Our purpose was to assess fetal central and regional hemodynamics in normal fetuses using two-dimensional, range-gated pulsed Doppler echocardiography in pregnant women on chronic baby aspirin regimen (87 mg). STUDY DESIGN: Fifteen fetuses exposed to maternal chronic ingestion of baby aspirin were compared with 26 control fetuses. Longitudinal studies of the umbilical artery waveform and blood flow through the fetal right and left ventricles were obtained every 4 weeks during gestation in a group of fetuses exposed to daily maternal intake of 87 mg of aspirin. Pulsed Doppler waveforms were obtained below the tricuspid and mitral valves, at the level of the descending aorta (below the ductus), and at the level of the fetal renal artery as it enters the kidney. All tracings were recorded on a strip chart and analyzed with a digital light-pen and graphic overlay system. Peak systolic velocity and minimal diastolic velocity were obtained for the umbilical and fetal renal artery. Peak flow velocity and velocity time integral of the pulsed Doppler waveforms of the atrioventricular valves were calculated. Acceleration time/ejection time ratio was obtained for the descending aorta. RESULTS: No significant differences were found among the two groups in either central or regional circulation. CONCLUSION: Chronic daily maternal ingestion of baby aspirin does not significantly affect the central and regional circulation of the fetus.

Fetal Circulatory System in Growth-Retarded Fetus with Late Decelerations and Oligohydramnios

We present 4 cases of growth-retarded fetuses with fetal heart rate late decelerations and oligohydramnios. Doppler ultrasound revealed significantly decreased pulsatility index (PI) values of the middle cerebral artery; however, the PI values of the renal artery, femoral artery and umbilical artery were within normal ranges in all fetuses. Relative redistributions in the fetal circulatory system were shown with fetal hypoxemia without acidosis.

The association between an abnormal nuchal skin fold, trisomy 21, and ultrasound abnormalities identified during the second trimester of pregnancy.

Fetal echocardiography and a detailed non-cardiovascular ultrasound examination were performed prospectively between 14 and 23 weeks of gestation prior to genetic amniocentesis in 2800 consecutive fetuses at increased risk for trisomy 21 due to advanced maternal age or a low maternal serum alpha-fetoprotein. An abnormal nuchal skin fold was defined as >or=6 mm. Of 2800 fetuses, 23 (0.82%) had an abnormal nuchal skin fold. Seven of 35 fetuses (20%) with trisomy 21 and one of 12 fetuses (8.3%) with trisomy 18 had an abnormal nuchal skin fold. Of the 23 fetuses with an abnormal nuchal skin fold, seven (30.4%) had trisomy 21, one (4.4%) trisomy 18, one (4.4%), 46,XY,11p+ and 14 (60.8%) had normal karyotypes. The fetuses with trisomy 18 and 46,XY,11p+ had malformations of the cardiovascular and non-cardiovascular organ systems. Five of seven (71%) fetuses with trisomy 21 and an abnormal nuchal skin fold had abnormalities of both the cardiovascular and non-cardiovascular organ systems; one of seven (14.5%) had a heart defect only; and one of seven (14.5%) an abnormality of a non-cardiovascular organ system. Of the 14 fetuses with an abnormal nuchal skin fold and normal karyotype, seven had no additional abnormalities, six an abnormality of the heart, and one a non-cardiovascular defect. Fetuses with an abnormal nuchal skin fold had a significant increased incidence of trisomy 21 when a combination of cardiovascular and non-cardiovascular abnormalities were present compared to fetuses with no additional defects or a single defect of the heart or non-cardiovascular organ system (p = 0.001). In fetuses with an abnormal nuchal skin fold, the incidence of congenital heart disease was 6155, central nervous system defects 17%, hyperechoic bowel 8.7%, and renal abnormalities 17.4%. These findings would suggest that the fetus identified with an abnormal nuchal skin fold with additional cardiovascular and non-cardiovascular abnormalities has a greater risk for chromosomal aneuploidy compared to the fetus with an isolated abnormal nuchal skin fold or with one additional abnormality of the heart or a non-cardiovascular organ system. When an abnormal nuchal skin fold is identified, careful evaluation of the fetal cardiovascular system should be made.

Maternal and fetal cardiovascular effects and placental transfer of the oxytocin antagonist atosiban in late-gestation pregnant sheep

Atosiban is a synthetic oxytocin antagonist that is currently undergoing dose-ranging clinical trials. To date, no data are available on the cardiovascular effects of combined oxytocin and vasopressin blockade during late pregnancy. Our aims were (1) to determine the effects of atosiban infusion on the maternal and fetal cardiovascular system and on uterine blood flow and (2) to determine the maternal pharmacokinetics and the rate of placental transfer of atosiban. Five chronically catheterized pregnant sheep were treated with a 2-hour infusion of atosiban (300 micrograms.min-1) at 116 to 126 days' gestation. Maternal and fetal blood pressure and heart rate and uterine blood flow were measured before and during the infusion. Maternal and fetal arterial blood samples were obtained throughout the experiment for measurement of plasma atosiban levels and blood gas values. No significant change in maternal cardiovascular parameters or uterine blood flow were observed. Similarly, no changes in fetal blood pressure and arterial blood gases were present during the infusion of the atosiban. Maternal plasma levels of atosiban reached a maximum of 585.2 +/- 82.2 (ng/ml mean +/- SD) at the end of the infusion and decreased biexponentially with a mean t1/2 alpha of 17 minutes and a mean t1/2 beta of 2.2 hours. Fetal plasma levels of atosiban were at or below the detection limit. Atosiban does not significantly affect maternal or fetal cardiovascular parameters when it is administered for 2 hours in late-pregnant sheep. Although significant levels were measured in maternal blood, negligible transfer to the fetus occurred.

Effects of Maternal Ingestion of Low-Dose Aspirin on the Fetal Cardiovascular System

Effects of Maternal Ingestion of Low-Dose Aspirin on the Fetal Cardiovascular System

Effects of maternal ingestion of low-dose aspirin on the fetal cardiovascular system

Our purpose was to assess fetal central and regional hemodynamics in normal fetuses using two-dimensional, range-gated pulsed Doppler echocardiography in pregnant women on chronic baby aspirin regimen (87 mg). Fifteen fetuses exposed to maternal chronic ingestion of baby aspirin were compared with 26 control fetuses. Longitudinal studies of the umbilical artery waveform and blood flow through the fetal right and left ventricles were obtained every 4 weeks during gestation in a group of fetuses exposed to daily maternal intake of 87 mg of aspirin. Pulsed Doppler waveforms were obtained below the tricuspid and mitral valves, at the level of the descending aorta (below the ductus), and at the level of the fetal renal artery as it enters the kidney. All tracings were recorded on a strip chart and analyzed with a digital light-pen and graphic overlay system. Peak systolic velocity and minimal diastolic velocity were obtained for the umbilical and fetal renal artery. Peak flow velocity and velocity time integral of the pulsed Doppler waveforms of the atrioventricular valves were calculated. Acceleration time/ejection time ratio was obtained for the descending aorta. No significant differences were found among the two groups in either central or regional circulation. Chronic daily maternal ingestion of baby aspirin does not significantly affect the central and regional circulation of the fetus.

Cardiovascular and pulmonary effects of betamethasone during midtrimester on fetal rats.

In order to elucidate the effects of corticosteroids on fetal hearts during midtrimester, pregnant rats were injected with a daily dose of betamethasone (1 mg/kg) from the 12th day through the 17th day of pregnancy. The fetal cardiovascular and pulmonary systems were studied on the 21st day of pregnancy (term). The treated fetuses showed the following signs of hydrops fetalis: retarded growth, pale, edematous skin, and decreased movement. The thymus and lung displayed prominent hypoplasia. The morphometry of the treated fetuses revealed: decreased right ventricle mass by 37% and decreased left ventricle mass by 29%. We concluded betamethasone had a significant effect on the developing fetal cardiovascular system, inducing hydrops fetalis. Additionally, beta-methasone caused hypoplasia of the thymus and lung.

妊娠と血液循環 胎児呼吸循環系の生理と低酸素血症に対する反応

妊娠と血液循環 胎児呼吸循環系の生理と低酸素血症に対する反応

Effect of caffeine on expression of cardiac myosin heavy chain gene in adult hypothyroid and fetal rats.

Changes in cardiac myosin heavy chain (MHC) gene expression and isozyme transitions have been shown to be caused by developmental changes, hemodynamic overload, or the activity of various hormones. In this study, to examine whether caffeine, which has teratogenic effects on the fetal cardiovascular system, causes the distribution of cardiac MHC phenotype and, if so, to evaluate the mechanisms of the distribution of cardiac MHC phenotype by caffeine, we examined the effects of caffeine, theophylline, and cAMP on the cardiac MHC isoform transitions at the gene and protein levels using hypothyroid adult rats. Furthermore, we examined the expression of alpha- and beta-MHC gene in cardiac muscles of fetuses whose dams had received caffeine. The results showed that caffeine, theophylline, and cAMP caused accumulations of alpha-MHC mRNA and MHC isozyme V1. Furthermore, in the fetal hearts, it was recognized that caffeine induced an accumulation of alpha-MHC gene expression, as was also seen in the dams. However, this effect of caffeine on the heart was stronger in the fetus than in the dam. Intracellular cAMP concentration was increased by the administration of caffeine, theophylline, or cAMP, and the levels showed a positive correlation with those of alpha-MHC mRNA. These results suggest that the induction of alpha-MHC mRNA expression by the administration of caffeine may be induced by an increase in intracellular cAMP concentration.

Fetal behavioral state and the cardiovascular system.

The desire to assess fetal well-being from be- recently, implantable ultrasonic transducers have havioral patterns leads to the need to un- made long-term measurements of absolute flow derstand the underlying control mechanisms and possible. Lastly, radiolabelled microspheres can the function of such patterns during fetal devel- be used to determine blood flow to discrete areas opment. The study of behavioral states is of or organs. Because flow is measured only at the greatest value in this context if it shows patho- time when the microspheres impact in the tissue, physiological changes. In giving the reason for the technique cannot be used to measure changes describing behavioral patterns in the neonate, from moment to moment. The necessity of using Prechtl’ stated that: a separate label for each time point, and the possible reduction in flow produced by the infarction out to be different in the various states, the states must itself, limits the number of observations that can not only be considered as a descriptive behuviour be made, usually to six per preparation. classification, but as distinct modes of brain activity. In this article we review the evidence that, with respect to the fetal cardiovascular system, the “functional properties of the nervous system” differ in the various states. In order to examine this, we draw on data from studies in which several variables were recorded over prolonged periods of time. As this has only been possible in the sheep fetus, we will confine our discussion to that species. The majority of information has been gained in late gestation, so it is inappropriate to discuss the development of behavior. However, this preparation does have the advantage that it can be chronically instrumented and studied for a number of weeks, without the in

Control of vascular resistance in the human placenta

An increase in blood flow on both sides of the placenta throughout gestation is necessary to maintain optimal placental and fetal growth. Inadequate blood flow to the placenta is associated with fetal and placental growth retardation. The normal increase in flow is achieved in both circulations of the placenta by a combination of altered vascular anatomy and changes in both vascular resistance and perfusion pressure. Perfusion pressure itself depends on systemic cardiovascular changes and so changes in the maternal or fetal cardiovascular systems may have profound effects on placental perfusion. This review, however, will deal with the contribution of vascular resistance within the placenta itself to placental blood flow. The hemomonochorial human placenta possesses no vascular response elements within the maternal side of the placenta per se. Rather the vascular response elements which control blood flow to the intervillous space of the placenta lie within the uterine, radial, basal and spiral arteries. As trophoblast invasion of the spiral arteries during the first and early second trimesters of pregnancy removes the musculo-elastic lining of the spiral arteries (Sheppard and Bonnar, 198 l), it is probable that these vessels lose their vascular reactivity. Therefore, blood flow into the intervillous space in normal pregnancy may depend more on vascular reactivity of the uterine, radial or basal arteries or on systemic cardiovascular events and so does not fall within the scope of this review of the control of placental vascular resistance. Ultrasound measurements of blood flow velocity waveforms in umbilical and uterine vessels are being increasingly used in the clinical setting as indices ofvascular impedance and flow to the placenta and, hence, of fetal well-being (Trudinger et al, 1985). In normal pregnancy, there is a progressive increase in umbilical end-diastolic velocity and thus a steady fall in resistance in the fetal-placental circulation (Erskine and Ritchie, 1985). The altered umbilical waveforms seen in pre-eclampsia and/or intrauterine growth retardation, which indicate increased fetal-placental vascular impedance and reduced flow, are associated with increased fetal and neonatal morbidity and mortality. Such observations have led to therapeutic interventions such as low-dose aspirin designed to improve fetal-placental blood flow and hence improve clinical outcome (Trudinger et al, 1988).