They attributed the findings to inferior vena caval occlusion, resulting in improper mixing of the dye Evans blue and extravasation of fluid into the lower extremities because of the elevated venous pressure.
As described earlier, DHEA-S is the precursor of placental estrogens, which may play a role in vasodilation through NO production, triggering a compensatory expansion of blood volume through the renin-angiotensin-aldosterone axis. The sudden appearance of spider angiomas during pregnancy is common, as is the occurrence of palmar erythema.
Both of these events are thought to be hormonally mediated. Burwell and Metcalfe 51 reported the rapid growth of a pre-existing arteriovenous fistula during pregnancy. Rupture of splanchnic artery aneurysms is more common in women than in men before the age of Most of these aneurysms rupture between the seventh and ninth months of pregnancy. The chance that a subarachnoid hemorrhage will occur increases with each trimester of pregnancy.
Histologic changes have been reported to occur in the wall of the aorta during pregnancy, 54 but whether or not these are related to vessel strength and contribute to aortic dissection or rupture is open to question. Neither the role played by the fetus nor that of the hypervolemia of pregnancy is known.
From the data presented in the literature, the sex steroid hormones must play an important part. Observations by Ueland and Parer 56 that the intravenous infusion of natural estrogens in nonpregnant ewes produces an increase in cardiac output similar to that encountered in pregnancy in the same animals support this theory.
In , Howard and colleagues 58 first published their data on the supine hypotensive syndrome of late pregnancy. They showed, by manometric measurements, that the fernoral venous pressure was highest when patients were in the supine position and attributed this to inferior vena caval occlusion by the gravid uterus. These findings later were confirmed by Scott and Kerr, 59 who studied pressure changes in the inferior vena cava in patients undergoing cesarean section.
In , Kerr and associates 60 convincingly showed, by angiographic techniques, total occlusion of the inferior vena cava late in pregnancy in a patient in the supine position. Two subsequent serial hemodynamic studies during pregnancy, using dye dilution techniques to estimate cardiac output, showed the effect of maternal posture.
The decline was entirely attributable to a drop in stroke volume because heart rate remained relatively constant. In the second trimester, the gravid uterus impairs venous return in standing women and can cause cardiovascular disturbances. Using aortography, Bieniarz and coworkers 62 showed that the arterial side of the vascular tree also was affected to some degree by the large gravid uterus at term.
They showed lateral displacement, attenuation, and elongation of the distal aorta as it was compressed against the maternal spine in supine recumbency. During hypotension, this effect becomes more pronounced. There is conflicting information in the literature regarding the maternal cardiorespiratory response to exercise. This controversy can be attributed in part to the different ways in which the patients were exercised, the maternal posture, and the techniques used to measure the hemodynamic response.
Standard treadmill exercise weight bearing is associated with higher rates of oxygen consumption in pregnant women than in women in the postpartum period. In a serial study by Ueland and associates, 9 the increment in cardiac output during mild, standardized, non—weight-bearing exercise on a bicycle ergometer was found to be the same throughout pregnancy and postpartum.
Serial measurements of blood oxygen transport during exercise in this same group of patients 64 showed that exercise of mild intensity was associated with an increased oxygen requirement and cost more in terms of oxygen consumption during pregnancy. In contrast, Knuttgen and Emerson 63 reported a slight decrease in oxygen consumption when a similar group of patients were studied in the pregnant and the nonpregnant state.
Metcalfe and colleagues 65 evaluated the effect of regular exercise before and during pregnancy and noted that neither the oxygen cost of steady-state exercise nor the oxygen debt incurred by exercise was elevated during pregnancy. With moderate exercise, the rise in cardiac output seems to be progressively smaller as pregnancy advances, suggesting a progressive decline in circulatory reserve. If the data of Robbe 66 are scrutinized carefully, a similar small increment in cardiac output in response to exercise is found to occur late in pregnancy.
M-Mode echocardiography suggests that cardiac output increases secondary to increased fractional shortening early in pregnancy. Increase in left ventricular end-diastolic volume is the primary reason for increased cardiac output within pregnancy, however. There does not seem to be any appreciable buildup in oxygen debt during pregnancy when compared with nonpregnant controls. The extent to which human uterine blood flow and oxygen consumption are altered by exercise during pregnancy is unclear.
Studies considering the response of cardiac output to exercise suggest, however, that cardiac output is fixed and increases at a rate that parallels oxygen demand. The augmented hemoglobin level enhances the blood oxygen-carrying capacity and serves to attenuate any possible reduction in oxygen delivery. Fetal heart tracings that were obtained from women during recovery from moderately strenuous exercise revealed no evidence of fetal distress although a consistent fetal tachycardia was noted.
This group of women also had fetal nonstress tests before and after exercise. All tests were reactive, and there was no significant difference in the monitoring time required to obtain a reactive nonstress test before and after exercise.
The hemodynamic responses to uterine contractions depend on the maternal posture in which they are studied.
There seems to be a remarkable degree of hemodynamic stability when the patient is on her side. Table 1 shows the similarities in peak hemodynamic values during a contraction in both positions studied.
The significant differences between contractions are attributable to the inferior vena caval occlusion caused by the gravid uterus. In addition to venous obstruction, contractions while in the supine position produce complete occlusion of the distal aorta or the common iliac arteries 73 ; the blood ejected by the left ventricle is distributed transiently only to the upper half of the vascular tree, resulting in an augmented response when measurements are taken in the upper extremities.
Arterial pressure measurements obtained from the femoral artery while in the supine position during a contraction show a marked decrease. Posture and uterine contractions. Am J Obstet Gynecol , Anesthesia plays a significant role in modifying the cardiovascular response to labor and delivery. In a series of patients undergoing hemodynamic studies throughout labor and delivery, substantial differences were noted between the group receiving local and paracervical block anesthetics and the group receiving a caudal anesthetic Table 2.
Anesthesia did not modify the profound changes accompanying delivery because the large increments in cardiac output for both groups from second stage to delivery were similar.
Early First Stage. Labor and delivery under local and caudal analgesia. The repetitive hemodynamic changes of uterine contraction during labor can be circumvented by cesarean section delivery. The significant increment in cardiac output accompanying delivery cannot be prevented, although it can be modified to some extent by the anesthetic technique employed.
Table 3 summarizes the changes in hemodynamics associated with surgical delivery using spinal anesthesia, balanced general anesthesia thiopental, succinylcholine, nitrous oxide , and epidural anesthesia with and without epinephrine. Some similarities should be stressed. The marked decrease in cardiac output and blood pressure after the induction of anesthesia was equivalent in the patients receiving a spinal anesthetic and in the patients receiving an epidural anesthetic with epinephrine.
In the balanced general anesthesia group, 79 there was good hemodynamic stability throughout surgery except at the time of intubation and extubation and when awakening the patient postoperatively.
During these procedures, there was a marked but transient elevation in cardiac output, heart rate, and blood pressure. The documented blood loss at vaginal delivery is approximately mL, and the loss at cesarean section is approximately mL. Table 4 summarizes the data of serial measurements of blood volume and hematocrit after delivery in a large number of patients. TABLE 3. Cesarean section under epidural anesthesia without epinephrine.
Cesarean section under subarachnoid block anesthesia. Cesarean section under thiopental, nitrous oxide, and succinylcholine anesthesia. TABLE 4. The decision to use certain substrates depends on both environmental conditions and substrate availability. For example, during strenuous exercise in which lactate concentrations are high in the blood, the heart predominantly utilizes lactate. Cardiac metabolism. Under pregnancy conditions, cardiomyocytes increase utilization of fatty acids while decreasing glucose utilization.
These reducing equivalents deliver electrons to the electron transport chain, which then couples the highly favourable reduction of free oxygen into water with the generation of a proton gradient across the inner mitochondrial membrane. Approximately one-third of cardiac volume is made up of mitochondria. Thus, precise regulation of the complex metabolic pathways within the heart is pivotal to ensure working and efficient mitochondria.
Mechanisms that dictate the choice of substrate by the heart remain incompletely understood. A leading factor in substrate choice is simply circulating substrate availability, reflecting the omnivorous nature of the heart. So, for example, high use of fatty acids during exercise reflects the high rate of lipolysis in adipose tissue and consequent elevated circulating triglycerides and free fatty acids.
But a number of additional regulatory mechanisms exist. Usually in response to insulin signalling, activated Akt triggers the translocation of glucose transporter type 4 GLUT4 -containing vesicles to the plasma membrane, thereby stimulating glucose uptake. In addition to allosteric enzyme regulation, control of metabolic flux in the heart is also regulated at the transcriptional level.
The peroxisome proliferator-activated receptors PPAR , members of the nuclear receptor family of transcription factors, have been most studied. CD36 , transport into the mitochondria e. In summary, the heart is profoundly dependent upon mitochondria and oxidative metabolism. Although it normally primarily consumes fatty acids, it can consume nearly any fuel type to satisfy its avid metabolic needs.
Cardiac metabolism is altered during pregnancy in order to accommodate both foetal needs and increased demands for cardiac work. The latter reflects the large haemodynamic shifts that occur during pregnancy.
Some uncertainty remains over the magnitude and direction of these shifts despite numerous studies because inconsistent experimental conditions have often led to contradictory measurements. For example, young healthy African Americans have lower resting cardiac indices and higher resting systemic vascular resistance than their Caucasian counterparts.
Despite these significant variabilities, some haemodynamic changes emerge as consistent and reproducible Figure 3. Both blood volume and red blood cell mass increase, leading to increased preload. In addition, the hormonal milieu of pregnancy leads to the secretion of various vasodilators, such as nitric oxide NO and prostaglandins, which cause a drop in the peripheral resistance.
Haemodynamics changes during pregnancy. Cardiac output, heart rate, stroke volume, and blood volume all increase between 5 and 8 weeks of gestation, peak by mid-pregnancy, and is sustained until the end of pregnancy. These parameters are reversed by 6 months postpartum. Cardiac function, both systolic and diastolic, must be affected by the increase in preload and decrease in afterload of pregnancy, but different studies surprisingly come to quite different conclusions.
The limited data on diastolic function during pregnancy have been inconsistent; some studies have reported a decrease in diastolic function near the end of pregnancy, while others have reported minor to no changes. On the other hand, it is clear that important morphological adaptations occur in the heart during pregnancy.
By the end of pregnancy, there is enlargement in all four chambers and all valves. These adaptations lead to eccentric hypertrophy during pregnancy. In summary, the heart of a pregnant woman faces significantly altered haemodynamic forces, likely demanding equally significant alterations in metabolism Table 1. The magnitude of these numerous haemodynamic and morphological changes differs significantly between studies, underscoring the need for further and more complete studies on this topic.
Maternal serum concentrations of energy substrates in non-pregnant controls, early, and late pregnancy. Remarkably little is known of the metabolic changes that occur in the heart during pregnancy. Studies in humans are almost non-existent.
How increased efficiency is achieved is not known. The increase in oxygen consumption is mostly accommodated by increased coronary blood flow, rather than increased extraction, and coronary arterioles become more sensitive to stress-induced vasodilation in pregnancy. The choice of fuel use by the heart also changes dramatically during pregnancy. Metabolic changes thus do not temporally parallel haemodynamic demands, but rather parallel foetal metabolic demands. Thus the heart, like skeletal muscle, exhibits relative insulin resistance during pregnancy.
The mechanisms underlying the above metabolic changes are not known. Morphological studies are scant and have not provided significant insights, other than the noted cardiac hypertrophy.
Mitochondria appear morphologically normal during pregnancy, both in intact animals and in isolated cardiomyocytes. Total levels of GLUT4 during pregnancy are decreased, 86 but levels at the plasma membrane have not been reported.
Another possible explanation may simply be the high influx of free fatty acids, which would be predicted to inhibit glucose consumption, as originally described by Randle et al. A few molecular studies have been undertaken. Cardiac endothelial nitric oxide synthase eNOS activity appears to increase during pregnancy, perhaps explaining the higher tendency of arterioles to dilate to sheer stress.
Akt and downstream mTOR are also activated in murine pregnancy, but which isoforms are responsible has not been teased apart. Finally, molecular changes also likely occur on the side of ATP consumption. For example, the late outward potassium current slows in late pregnant rats and mice, likely explaining the prolonged QT interval seen on ECGs. Pregnancy also drastically alters the maternal hormonal milieu, including dramatic increases in oestrogen, progesterone, prolactin, and placental hormones.
As noted above, many of these have been implicated in causing systemic insulin resistance during pregnancy, but their effects on cardiac metabolism during pregnancy have not been studied.
The effect of oestrogen on fatty acid metabolism has been explored in the context of hormone replacement therapy, where it appears to increase cardiac fatty acid utilization while not affecting glucose metabolism. Clearly, molecular understanding of metabolic changes in the maternal heart during pregnancy is in its infancy. Key questions remain unanswered. What upstream mechanisms drive metabolic changes? How do the observed metabolic changes interrelate with morphological changes?
How do metabolic alterations during pregnancy reset after delivery? Few data exist on cardiac metabolic changes in the postpartum stage. Are the cardiac metabolic changes of pregnancy beneficial or harmful to the heart? That is, is maternal cardiac metabolism rendered vulnerable in deference to the imperatives of foetal development? Does aberrant cardiac metabolism contribute to cardiac diseases of pregnancy?
Myocardial infarction during late pregnancy and the peripartum period is increasingly common, due in part to rising maternal age and other lifestyle changes. One strong possibility is that this susceptibility stems from the dramatically higher reliance on fatty acid oxidation, which, in other pathological contexts, has been shown to be detrimental. PPCM is another rare but potentially fatal cardiac complication of pregnancy. The disease is characterized by systolic heart failure presenting in the last month of pregnancy or the first 5 months postpartum.
Recent work has strongly supported the notion that PPCM is caused by vasculo-metabolic dysfunction, triggered by the unique hormonal environment of late pregnancy. At least two complementary mechanisms are proposed to contribute. The first mechanism was uncovered using mice genetically engineered to lack the transcription factor STAT3 in cardiomyocytes. In these mice, the late-gestational hormone prolactin is aberrantly cleaved in the heart to a 16 kDa fragment that is toxic to the cardiac vasculature.
Vascular dropout and cardiomyopathy ensue. In these mice, reduced cardiac expression of the angiogenic factor VEGF renders the heart susceptible to secretion from the late gestational placenta of soluble Flt1 sFlt1 , an endogenous decoy receptor and VEGF inhibitor.
The outcome is, again, vascular dropout and PPCM. These models are complementary and explain a number of clinical observations. PPCM is a disease of late pregnancy and early postpartum, which does not coincide with the onset of haemodynamic stresses of pregnancy see above. Instead, these models propose that PPCM is triggered by hormones specific to the late gestational period: prolactin from the pituitary and sFlt1 from the placenta.
There are likely others as well. Clinically, pre-eclampsia causes cardiac dysfunction directly, independently of blood pressure, and frequently presents with congestive heart failure. Could metabolic changes be causative for PPCM? As outlined above, strong evidence from two mouse models points to PPCM being at least in part a disease of metabolic insufficiency caused by loss of sufficient delivery of fuel and oxygen to the heart.
Other mechanisms likely also exist, such as direct toxicity to the heart by the affected vasculature. For example, 16 kDa prolactin causes vessels to secrete the micro-RNA miRa, which in turn triggers apoptosis in adjoining cardiomyocytes. Since the gestational heart is increasingly dependent on fatty acid oxidation as primary source of fuel, aberrant fatty acid oxidation in these mice is likely to contribute to PPCM.
To what extent this occurs in human cardiomyopathy remains an open question. Another critical and still open question is what renders one in a thousand women susceptible to these hormonal insults, while the rest tolerate pregnancy well. How the heart reacts metabolically to these insults remains unstudied and an inability to appropriately remodel metabolically may define the predisposition to PPCM. There may also be a genetic predisposition.
PPCM does not follow clear Mendelian inheritance, but some familial associations have been noted. Finally, the host predisposition may also be acquired, thus, for example, by a coincident myocarditis that removes cardiac defences against the hormonal insults described above. Viral infection has long been thought to contribute to PPCM. Combined with a decrease in fibrinolytic activity, these changes tend to prevent excessive bleeding at delivery.
Thus, pregnancy is a relatively hypercoagulable state, but during pregnancy neither clotting or bleeding times are abnormal.
Cardiac Output increases to a similar degree as the blood volume. During labor , further increases are seen with pain in response to increased catecholamine secretion; this increase can be blunted with the institution of labour analgesia.
Also during labour, there is an increase in intravascular volume by ml of blood from the contracting uterus to the venous system. The heart is enlarged by both chamber dilation and hypertrophy. Upward displacement of the diaphragm by the enlarging uterus causes the heart to shift to the left and anteriorly. Blood Pressure. Systemic arterial pressure is never increased during normal gestation. In fact, by midpregnancy, a slight decrease in diastolic pressure can be recognized.
Pulmonary arterial pressure also maintains a constant level. However, vascular tone is more dependent upon sympathetic control than in the nonpregnant state, so that hypotension develops more readily and more markedly consequent to sympathetic blockade following spinal or extradural anaesthesia.
Central venous and brachial venous pressures remain unchanged during pregnancy, but femoral venous pressure is progressively increased due to mechanical factors.
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