BAB I

A. Hemodynamic Function in Pregnancy

Cardiovascular System The pregnancy-induced changes in the cardiovascular system
develop primarily to meet the increased metabolic demands of the mother and fetus.
Blood Volume
Blood Volume increases progressively from 6-8 weeks gestation (pregnancy) and reaches a
maximum at approximately 32-34 weeks with little change there after. Most of the added
volume of blood is accounted for by an increased capacity of the uterine, breast, renal,
striated muscle and cutaneous vascular systems, with no evidence of circulatory overload in
the healthy pregnant woman. The increase in plasma volume (40-50%) is relatively greater
than that of red cell mass (20-30%) resulting in hemodilution and a decrease in hemoglobin
concentration. Intake of supplemental iron and folic acid is necessary to restore hemoglobin
levels to normal (12 g/dl). The increased blood volume serves two purposes. First, it
facilitates maternal and fetal exchanges of respiratory gases, nutrients and metabolites.
Second, it reduces the impact of maternal blood loss at delivery. Typical losses of 300-500 ml
for vaginal births and 750-1000 ml for Caesarean sections are thus compensated with the socalled "autotransfusion" of blood from the contracting uterus.
Blood Constituents
Red cell mass is increased 20-30%. Since plasma volume increases early in pregnancy and
faster than red blood cell volume, the hematocrit falls until the end of the second trimester,
when the increase in the red blood cells is synchronized with the plasma volume increase.
The hematocrit then stabilizes or may increase slightly near term. Leukocyte counts are
variable during gestation, but usually remain within the upper limits of normal. Marked
Page27 elevations, however, develop during and after parturition (delivery). Fibrinogen, as
well as total body and plasma levels of factors VII, X and XII increases markedly. The
number of platelets also rises, yet not above the upper limits of normal. Combined with a
decrease in fibrinolytic activity, these changes tend to prevent excessive bleeding at delivery.
The placenta may be partially responsible for this alteration in fibrinolytic status.
Plasminogen levels increase concomitantly with fibrinogens levels, causing an equilibration

of clotting and lysing activity. Thus, pregnancy is a relatively hypercoagulable state, but
during pregnancy neither clotting nor bleeding times are abnormal.
Cardiac Output
Cardiac Output increases to a similar degree as the blood volume. During the first trimester
cardiac output is 30-40% higher than in the nonpregnant state. Steady rises are shown on
Doppler echocardiography, from an average of 6.7 liters/minute at 8-11 weeks to about 8.7
liters/minute flow at 36-39 weeks; they are due, primarily, to an increase in stroke volume
(35%) and, to a lesser extent, to a more rapid heart rate (15%). There is a steady reduction in
systemic vascular resistance (SVR) which contributes towards the hyperdynamic circulation
observed in pregnancy. During labor, further increases are seen with pain in response to
increased catecholamine secretion; this increase can be blunted with the institution of labor
analgesia. Also during labor, there is an increase in intravascular volume by 300-500 ml of
blood from the contracting uterus to the venous system. Following delivery this
autotransfusion compensates for the blood losses and tends to further increase cardiac output
by 50% of predelivery values. At this point, stroke volume is increased while heart rate is
slowed.
Cardiac Size/Position/ECG
There are both size and position changes which can lead to changes in ECG appearance. The
heart is enlarged by both chamber dilation and hypertrophy. Dilation across the tricuspid
valve can initiate mild regurgitant flow causing a normal grade I or II systolic murmur.
Upward displacement of the diaphragm by the enlarging uterus causes the heart to shift to the
left and anteriorly, so that the apex beat is moved outward and upward. The size of the heart
appears to increase by about 12%. These changes lead to common ECG findings of left axis
deviation, sagging ST segments and frequently inversion or flattening of the T-wave in lead
III.
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. Page27 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 anesthesia. Central venous and brachial venous pressures remain unchanged
during pregnancy, but femoral venous pressure is progressively increased due to mechanical
factors.
Aortocaval Compression
From mid-pregnancy, the enlarged uterus compresses both the inferior vena cava and the
lower aorta when the patient lies supine. Obstruction of the inferior vena cava reduces venous
return to the heart leading to a fall in cardiac output by as much as 24% towards term. In the
unanaesthetised state, most women are capable of compensating for the resultant decrease in
stroke volume by increasing systemic vascular resistance and heart rate. There are also
alternative venous pathways, the paravertebral and azygos systems. During anesthesia,
however, these compensatory mechanisms are reduced or abolished so that significant
hypotension may rapidly develop. Obstruction of the lower aorta and its branches causes
diminished blood flow to kidneys, uteroplacental unit and lower extremities. During the last
trimester, maternal kidney function is markedly lower in the supine than in the lateral
position. Furthermore, the fetus is compromised by insufficient transplacental gas exchange.
Venous Distension
Venous distension increases approximately to 150% during the course of gestation and the
venous ends of capillaries become dilated, causing reduced blood flow. These vascular
changes contribute to delayed absorption of subcutaneously or intramuscularly injected
substances. Distension of the extradural veins heightens the risk of vascular damage during
institution of a regional block. The increased venous volume within the rigid spinal canal
reduces the volume or capacity of the extradural and intrathecal spaces for local anesthetic
solutions. This will therefore increase the spread of injected drugs.
Effects of the Labor on the Cardiovascular System
When a patient is the supine position, uterine contractions can cause a 25% increase in
maternal cardiac output, a 15% decrease in heart rate, and a resultant 33% increase in stroke
volume. However when the laboring patient is in the later recumbent position, the
hemodynamic parameters stabilize , with only a 7,6% increase in cardiac output, a 0,7%
decrease in heart rate, and a 7,7% increase in stroke volume. These significant differences are
attributable to inferior vena caval occlusion caused by the gravid uterus. During contractions,
pulse pressure increases 26% in the supine position but only 6% Page27 in the lateral

recumbent position. Central venous pressure increases in direct relationship to the intensity of
uterine contraction and increased intraabdominal pressure. Additionally, cardiopulmonary
blood volume increases 300-500mLduring contractions. At the time of delivery,
hemodynamic alterations vary with the anesthetic used.

Metabolism
All metabolic functions are increased during pregnancy to provide for the demands of fetus,
placenta and uterus as well as for the gravida's increased basal metabolic rate and oxygen
consumption. Protein metabolism is enhanced to supply substrate for maternal and fetal
growth. Fat metabolism increases as evidenced by elevation in all lipid fractions in the blood.
Carbohydrate metabolism, however, demonstrates the most dramatic changes. Metabolically
speaking, pregnant women live in a state of "accelerated starvation." First, nutritional
demands of the growing fetus are met by the intake of glucose and, second, secretion of
insulin in response to glucose is augmented. As early as 15 weeks of gestation, maternal
blood glucose levels after an overnight fast are considerably lower than in the nongravid
state. As the fetus and placenta grow and place increasing demands on the mother,
phenomenal alterations in metabolism occur. The most obvious physical changes are weight
gain and altered body shape. Weight gain is due not only to the uterus and its contents but
also to increase breast tissue, blood and water volume in the form of extravascular and
extracellular fluid. Deposition of fat and protein and increased cellular water are added to the
maternal stores. The average weight gain during pregnancy is 12,5Kg. During normal
pregnancy, approximately 1000g of weight gain is attributable to protein. Half of this is found
in the fetus and the placenta, with the rest being distributed as uterine contractile protein,
breast glandular tissue, plasma protein, and hemoglobin. Plasma albumin levels are decreased
and fibrinogen levels increased. Total body fat increases during pregnancy, but the amount
varies with total weight gain. During the second half of pregnancy, plasma lipids increase, but
triglycerides, cholesterol and lipoproteins decrease soon after delivery. The ratio of low
density lipoproteins to high density lipoproteins increases during pregnancy. Hypoglycemia
Optimal blood glucose levels in pregnant women range between 4.4 to 5.5 mmol/1 (80 to
100mg/dl). In healthy non-pregnant individuals, signs of hypoglycemia usually begin when
the blood glucose level declines to approximately 2.2 mmol/1 (40mg/dl); in pregnant women,
however, hypoglycemia is defined as a concentration below 3.3 mmol/1 (60mg/dl).

Hypoglycemia initiates the release of glucagon, cortisol and, importantly, catecholamines. In

the anaesthetized state, however, these compensatory mechanisms, particularly the release of
epinephrine (adrenaline), are blocked. Autonomic derangements in the form of hypotension
and tachycardia tend to ensue during high regional blockade or deep general anesthesia,
which may mask the symptoms and signs of hypoglycemia.

William
METABOLIC CHANGES
In response to the increased demands of the rapidly growing fetus and placenta, the pregnant
woman undergoes metabolic changes that are numerous and intense. Certainly no other
physiological event induces such profound metabolic alterations. By the third trimester,
maternal basal metabolic rate is increased by 10 to 20 percent compared with that of the
nonpregnantstate. This is increased by an additional 10 percentin women with a twin
gestation (Shinagawa, 2005). Viewed another way, an analysis by the World Health
Organization (2004) estimates that the additional total pregnancy energy demands associated
with normal pregnancy are approximately 77,000 kcal or 85 kcal/day, 285 kcal/day, and 475
kcal/dayduring the first, second, and third trimester, respectively
(Table 4-1). In addition to the corresponding increased caloric requirements, Lf (2011)
found that the increased energy demands were also compensated for, in part, by normal
pregnant women gravitating to less physically demanding
activities.
Weight Gain
Most of the normal increase in weight during pregnancy is attributable to the uterus and its
contents, the breasts, and increases in blood volume and extravascular extracellular fluid. A
smaller fraction results from metabolic alterations that increase accumulation of cellular
water, fat, and proteinsocalled maternal reserves. Hytten (1991) reported that the average
weight gain during pregnancy is approximately 12.5 kg or 27.5 lb (Table 4-2). Maternal
aspects of weight gain are considered in greater detail in Chapter 9 (p. 177).
Water Metabolism
Increased water retention is a normal physiological alteration of pregnancy. It is mediated, at
least in part, by a fall in plasma osmolality of approximately 10 mOsm/kg induced by a
resetting of osmotic thresholds for thirst and vasopressin secretion (Heenan, 2003;

Lindheimer, 1995). As shown in Figure 4-4, this phenomenon is functioning by early

pregnancy. At term, the water content of the fetus, placenta, and amnionic fluid approximates
3.5 L. Another 3.0 L accumulates from increases in maternal blood volume and in the size of
the uterus and breasts. Thus, the minimum amount of extra water that the average woman
accrues during normal pregnancy is approximately 6.5 L. Clearly demonstrable pitting edema
of the ankles and legs is seen in most pregnant women, especially at the end of the day. This
fluid accumulation, which may amount to a
liter or so, is caused by increased venous pressure below the level of the uterus as a
consequence of partial vena cava occlusion. A decrease in interstitial colloid osmotic pressure
induced by normal pregnancy also favors edema late in pregnancy(Oian, 1985). Longitudinal
studies of body composition have shown a progressive increase in total body water and fat
mass during pregnancy. Both initial maternal weight and weight gained during pregnancy are
highly associated with birthweight. It is unclear, however, what role maternal fat or water
have in fetal growth. Studies in well-nourished women suggest that maternal body water,
rather than fat, contributes more significantly to infant birthweight (Lederman, 1999;
Mardones-Santander, 1998).
Protein Metabolism
The products of conception, the uterus, and maternal blood are relatively rich in protein rather
than fat or carbohydrate.At term, the fetus and placenta together weigh about 4 kg and
contain approximately 500 g of protein, or about half of the total pregnancy increase (Hytten,
1971). The remaining 500 g is added to th e uterus as contractile protein, to the breasts
primarily in the glands, and to maternal blood as hemoglobin and plasma proteins.
Amino acid concentrations are higher in the fetal than in the maternal compartment (Cetin,
2005; van den Akker, 2009). This increased concentration is largely regulated by the placenta.
The placenta not only concentrates amino acids into the fetal circulation, but also is involved
in protein synthesis, oxidation, and transamination of some nonessential amino acids (Galan,
2009). Mojtahedi and associates (2002) measured nitrogen balance
across pregnancy in 12 healthy women. It increased with gestational age and thus suggested a
more efficient use of dietary protein.They also found that urinary excretion of 3methylhistidine did not change, indicating that maternal muscle breakdown is not required to
meet metabolic demands. Further support that pregnancy is associated with nitrogen
conservation comes from Kalhan and coworkers (2003), who found that the turnover
rate of nonessential serine decreases across gestation. The daily requirements for dietary
protein intake during pregnancy are discussed in Chapter 9 (p. 179).

 Carbohydrate Metabolism
Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial
hyperglycemia, and hyperinsulinemia (Fig. 4-5). is associated with several unique responses
to glucose ingestion. For example, after an oral glucose meal, gravid women demonstrate
prolonged hyperglycemia and hyperinsulinemia as well asa greater suppression of glucagon
(Phelps, 1981). This cannot be explained by an increased metabolism of insulin because its
halflife during pregnancy is not changed (Lind, 1977). Instead, this response is consistent
with a pregnancy-induced state of peripheral insulin resistance, the purpose of which is likely
to ensure a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in
late normal pregnancy is 45 to 70 percent lower than that of nonpregnant women (Butte,
2000; Freemark, 2006). The mechanism(s) responsible for insulin resistance is not
completely understood. Progesterone and estrogen may act, directly or indirectly, to mediate
this insensitivity. Plasma levels of placental lactogen increase with gestation, and this protein
hormone is characterized by growth hormonelike action. Higher levels may increase
lipolysis and liberation of free fatty acids (Freinkel, 1980). The increased concentration of
circulating free fatty acids also may aid increased tissue resistance to insulin (Freemark,
2006). The pregnant woman changes rapidly from a postprandial state characterized by
elevated and sustained glucose levels to a fasting state characterized by decreased plasma
glucose and some amino acids. Simultaneously, plasma concentrations of free fatty acids,
triglycerides, and cholesterol are higher. Freinkel and colleagues (1985) have referred to this
pregnancy-induced
switch in fuels from glucose to lipids as accelerated starvation. Certainly, when fasting is
prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly
appears.
Fat Metabolism
The concentrations of lipids, lipoproteins, and apolipoproteinsin plasma increase appreciably
during pregnancy (Appendix, p. 1291). Increased insulin resistance and estrogen stimulation
during pregnancy are responsible for the maternal hyperlipidemia. As reviewed by Ghio and
associates (2011), increased lipid synthesis and food intake contribute to maternal fat
accumulation during the first two trimesters. In the third trimester, however, fat storage
declines or ceases. This is a consequence of enhanced lipolytic activity, and decreased
lipoprotein lipase
activity reduces circulating triglyceride uptake into adipose tissue. This transition to a
catabolic state favors maternal use of lipids as an energy source and spares glucose and amino

acids for the fetus. Maternal hyperlipidemia is one of the most consistent and striking
changes of lipid metabolism during late pregnancy. Triacylglycerol and cholesterol levels in
very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and highdensity
lipoproteins (HDLs) are increased during the third trimester compared with those in
nonpregnant women. During the third trimester, average total serum cholesterol, LDLC,
HDL-C, and triglyceride levels are approximately 267 30 mg/dL, 136 33 mg/dL, 81 17
mg/dL, and 245 73 mg/ dL, respectively (Lippi, 2007). After delivery, the concentrations of
these lipids, as well as lipoproteins and apolipoproteins, decrease. Lactation speeds the
change in levels of many of these
(Darmady, 1982).
Hyperlipidemia is theoretically a concern because it is associated with endothelial
dysfunction. From their studies, however, Saarelainen and coworkers (2006) found that
endotheliumdependent vasodilation responses actually improve across pregnancy. This was
partly because increased HDL-cholesterol concentrations likely inhibit LDL oxidation and
thus protect the endothelium. Their findings suggest that the increased cardiovascular
disease risk in multiparous women may be related to factors other than maternal
hypercholesterolemia.
Leptin
In nonpregnant humans, this peptide hormone is primarily secreted by adipose tissue. It plays
a key role in body fat and energy expenditure regulation. Leptin deficiency is associated with
anovulation and infertility, however, pregnancy in a woman with a leptin-receptor mutation
has been reported (Maguire, 2012; Nizard, 2012).
Maternal serum leptin levels increase and peak during the second trimester and plateau until
term in concentrations two to four times higher than those in nonpregnant women. This
increase is only partially due to pregnancy weight gain, because leptin also is produced in
significant amounts by the placenta (Maym, 2011). Moreover, and as discussed in Chapter 5
(p. 106), placental weight is significantly correlated with leptin levels measured in umbilical
cord blood (Pighetti, 2003). Hauguel-de Mouzon and associates (2006) have hypothesized
that increased leptin production may be critical for the regulation of increased maternal
energy demands. As discussed in Chapter 48 (p. 961), leptin and adiponectina cytokine
involved with energy homeostasis and lipid metabolismmayalso help to regulate fetal
growth (Henson, 2006; Karakosta, 2010; Nakano, 2012). As reviewed by Miehle and

colleagues (2012), abnormally elevated leptin levels have been associated with preeclampsia
(Chap. 40, p. 729) and gestational diabetes (Chap. 57, p. 1136).
Ghrelin
This peptide is secreted principally by the stomach in response to hunger. It cooperates with
other neuroendocrine factors, such as leptin, in energy homeostasis modulation. It is also
expressed in the placenta and likely has a role in fetal growth and cell proliferation (Chap. 5,
p. 105). Maternal serum ghrelin levels increase and peak at midpregnancy and then decrease
until term (Fuglsang, 2008). This is explicable in that ghrelin levels are known to be
decreased in other insulin-resistant states such as metabolic syndrome and gestational
diabetes mellitus (Baykus, 2012; Riedl, 2007).

Muccioli and coworkers (2011) have

provided an excellent review of the many functions of ghrelin in the regulation of

reproductive function.
Electrolyte and Mineral Metabolism
During normal pregnancy, nearly 1000 mEq of sodium and 300 mEq of potassium are
retained (Lindheimer, 1987). Although the glomerular filtration of sodium and potassium is
increased, the excretion of these electrolytes is unchanged during pregnancy as a result of
enhanced tubular resorption (Brown, 1986, 1988).
And although there are increased total accumulations of sodium and potassium, their serum
concentrations are decreased slightly because of expanded plasma volume (Appendix, p.
1289). Still, these levels remain very near the normal range for nonpregnant women
(Kametas, 2003a). Total serum calcium levels, which include both ionized and nonionized
calcium, decline during pregnancy. This reduction follows lowered plasma albumin
concentrations and, in turn, a consequent decrease in the amount of circulating proteinbound
nonionized calcium. Serum ionized calcium levels, however, remain unchanged (Power,
1999). The developing fetus imposes a significant demand on maternal calcium homeostasis.
For example, the fetal skeleton accretes approximately 30 g of calcium by term, 80 percent of
which is deposited during the third trimester. This demand is largely met by a doubling of
maternal intestinal calcium absorption mediated, in part, by 1,25-dihydroxyvitamin D3
(Kovacs, 2006). In addition, dietary intake of sufficient calcium is necessary to prevent
excess depletion from the mother (Table 9-6, p. 179). This is especially important for
pregnant adolescents, in whom bones are still developing (Repke, 1994). Serum magnesium
levels also decline during pregnancy. Bardicef and colleagues (1995) concluded that
pregnancy is actually a state of extracellular magnesium depletion. Compared with

nonpregnant women, they found that both total and ionized magnesium concentrations were
significantly lower during normal pregnancy. Serum phosphate levels lie within
thenonpregnant range (Kametas, 2003a). The renal threshold for inorganic phosphate
excretion is elevated in pregnancy due increased calcitonin levels (Weiss, 1998). Iodine
requirements increase during normal pregnancy for several reasons (Leung, 2011;
Zimmermann, 2012). First, maternal thyroxine (T4) production increases to maintain
maternal euthyroidism and to transfer thyroid hormone to the fetus early in gestation before
the fetal thyroid is functioning (Chap. 58, p. 1147). Second, fetal thyroid hormone production
increases during the second half of pregnancy. This contributes
to increased maternal iodine requirements because iodide readily crosses the placenta. Third,
the primary route of iodine excretion is through the kidney. Beginning in early pregnancy, the
iodide glomerular filtration rate increases by 30 to 50 percent. Thus, because of increased
thyroid hormone production, the iodine requirement of the fetus, and greater renalclearance,
dietary iodine requirements are higher during normal gestation. Moreover, Burns and
associates (2011) have reported that the placenta has the ability to store iodine. Whether
placental
iodine functions to protects the fetus from inadequate maternal dietary iodine, however, is
currently unknown. Iodine deficiency is discussed later in this chapter (p. 69) as well as in
Chapter 58 (p. 1155). With respect to most other minerals, pregnancy induces little change in
their metabolism other than their retention in amounts equivalent to those needed for growth
(Chap. 7,p. 134 and Chap. 9, p. 179). An important exception is the considerably increased
requirement for iron, which is discussed subsequently.