HEMATOLOGICAL CHANGES

Blood Volume
The well-known hypervolemia associated with normal pregnancy averages 40 to 45 percent
above the nonpregnant blood volume after 32 to 34 weeks (Pritchard, 1965; Zeeman, 2009).
In individual women, expansion varies considerably. In some there is only a modest increase,
whereas in others the blood volume nearly doubles. A fetus is not essential for this because
increased blood volume develops in some women with hydatidiformmole.
Pregnancy-induced hypervolemia has several important functions. First, it meets the
metabolic demands of the enlarged uterus and its greatly hypertrophied vascular system.
Second, it provides abundant nutrients and elements to support the rapidly growing placenta
and fetus. Increased intravascular volume also protects the mother, and in turn the fetus,
against the deleterious effects of impaired venous return in the supine and erect positions.
Last, it safeguards the mother against the adverse effects of parturition-associated blood loss.
Maternal blood volume begins to increase during the first trimester. By 12 menstrual weeks,
plasma volume expands by approximately 15 percent compared with that of prepregnancy
(Bernstein, 2001). As shown in Figure 4-6, maternal blood volume expands most rapidly
during the second trimester. It then rises at a much slower rate during the third trimester to
plateau during the last several weeks of pregnancy. Blood volume expansion results from an
increase in both plasma and erythrocytes. Although more plasma than erythrocytes is usually
added to the maternal circulation, the increase in erythrocyte volume is considerable and
averages 450 mL (Pritchard, 1960). Moderate erythroid hyperplasia is present in the bone
marrow, and the reticulocyte count is elevated slightly during normal pregnancy. As discussed
in Chapter 56 (p. 1101), these changes are almost certainly related to an elevated maternal
plasma erythropoietin level. This peaks early during the third trimester and corresponds to
maximal erythrocyte production (Clapp, 2003; Harstad,
1992).
Hemoglobin Concentration and Hematocrit
Because of great plasma augmentation, hemoglobin concentration and hematocrit decrease
slightly during pregnancy (Appendix, p. 1287). As a result, whole blood viscosity decreases
(Huisman, 1987). Hemoglobin concentration at term averages 12.5 g/dL, and in
approximately 5 percent of women, it is below 11.0 g/dL (Fig. 56-1, p. 1102). Thus, a
hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, should be
considered abnormal and usually due to iron deficiency rather than pregnancy hypervolemia.
Iron Metabolism

Storage Iron
The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half
that found normally in men. Most of this is incorporated in hemoglobin or myoglobin, and
thus, iron stores of normal young women are only approximately 300 mg (Pritchard, 1964).
Iron Requirements
Of the approximate 1000 mg of iron required for normal pregnancy, about 300 mg are
actively transferred to the fetus and placenta, and another 200 mg are lost through various
normal excretion routes, primarily the gastrointestinal tract. These are obligatory losses and
accrue even when the mother is iron deficient. The average increase in the total circulating
erythrocyte volumeabout 450 mLrequires another 500 mg. Recall that each 1 mL of
erythrocytes contains 1.1 mg of iron. Because most iron is used during the latter half of
pregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7
mg/day (Pritchard, 1970). In most
women, this amount is usually not available from iron stores. Thus, without supplemental
iron, the optimal increase in maternal erythrocyte volume will not develop, and the
hemoglobin concentration and hematocrit will fall appreciably as plasma volume increases.
At the same time, fetal red cell production is not impaired because
the placenta transfers iron even if the mother has severe iron deficiency anemia. In severe
cases, we
have documented maternal hemoglobin values of 3 g/dL, and at the same time, fetuses had
hemoglobin
concentrations of 16 g/dL. The complex mechanisms of placental iron transport and
regulation
have recently been reviewed by Gambling (2011) and Lipiski (2013) and all of their
coworkers. It follows that the amount of dietary iron, together with that mobilized from
stores, will be
insufficient to meet the average demands imposed by pregnancy. If the nonanemic pregnant
woman is not given supplemental iron, then serum iron and ferritin concentrations decline
after midpregnancy. The early pregnancy increases in serum iron and ferritin are likely due to
minimal early iron demands combined with the positive iron balance from amenorrhea
(Kaneshige, 1981).
The Puerperium

Generally, not all the maternal iron added in the form of hemoglobin is lost with normal
delivery. During vaginal delivery and the first postpartum days, only approximately half of
the added
erythrocytes are lost from most women. These normal losses are from the placental
implantation site, episiotomy or lacerations, and lochia. On average, maternal erythrocytes
corresponding to approximately 500 to 600 mL of predelivery whole blood are lost with
vaginal delivery of a single fetus (Pritchard, 1965; Ueland, 1976). The average blood loss
associated with cesarean delivery or with the vaginal delivery of twins is approximately 1000
mL (Fig. 41-1, p. 781).
Immunological Functions
Pregnancy is thought to be associated with suppression of various humoral and cell-mediated
immunological functions to accommodate the foreign semiallogeneic fetal graft (Redman,
2014; Thellin, 2003). This is discussed further in Chapter 5 (p. 97). In reality, pregnancy is
both a proinflammatory and antiinflammatory condition, depending upon the stage of
gestation. Indeed, Mor and colleagues (2010, 2011) have proposed that pregnancy can be
divided into three distinct immunological phases. First, early pregnancy is proinflammatory.
During implantation and placentation, the blastocyst must break through the uterine cavity
epithelial
lining to invade endometrial tissue. Trophoblast must then replace the endothelium and
vascular smooth muscle of the maternal blood vessels to secure an adequate blood supply for
the placenta (Chap. 5, p. 90). All these activities create a veritable battleground of invading
cells, dying cells, and repairing cells. And, an inflammatory environment is required to secure
cellular debris removal and adequate repair of the uterine epithelium. In contrast,
midpregnancy is antiinflammatory. During this period of rapid fetal growth and development,
the predominant immunological feature is induction of an antiinflammatory state. Last,
parturition is characterized byan influx of immune cells into the myometrium to promote
recrudescence of an inflammatory process. An important antiinflammatory component of
pregnancy appears to involve suppression of T-helper (Th) 1 and T-cytotoxic (Tc) 1 cells,
which decreases secretion of interleukin-2 (IL- 2), interferon-, and tumor necrosis factor(TNF-). There is also evidence that a suppressed Th1 response is requisite for pregnancy
continuation. It also may explain pregnancy-related remission of some autoimmune disorders
such as rheumatoid arthritis, multiple sclerosis, and Hashimoto thyroiditiswhich are Th1mediated diseases (Kumru, 2005). As discussed in Chapter 40 (p. 733), failure of Th1
immune suppression may be related to preeclampsia development ( Jonsson, 2006). In

contrast to suppression of Th1 cells, there is upregulation of Th2 cells to increase secretion of
IL-4, IL-6, and IL-13 (Michimata, 2003). In cervical mucus, peak levels of immunoglobulins
A and G (IgA and IgG) are significantly higher during pregnancy. Similarly, the amount of
interleukin-1found in cervical and vaginal mucus during the first trimester is
approximately tenfold greater than that in nonpregnant women (Anderson, 2013).
Leukocytes
Beginning in the second trimester and continuing throughout pregnancy, some
polymorphonuclear leukocyte chemotaxis and adherence functions are depressed (Krause,
1987). Although incompletely understood, this activity suppression may be partly related to
the finding that relaxin impairs neutrophil activation (Masini, 2004). It is possible that these
depressed leukocyte functions also account in part for the improvement
of some autoimmune disorders. As shown in the Appendix (p. 1287), leukocyte count ranges
during pregnancy are higher than nonpregnant values, and the upper values approach
15,000/L. During labor and the early puerperium, values may become markedly elevated,
attaining levels of 25,000/L or even more. However,values
average 14,000 to 16,000/L (Taylor, 1981). The cause for this marked increase is not
known, but the same response occurs during and after strenuous exercise. It probably
represents the reappearance of leukocytes previously shunted out of active circulation. In
addition to normal variations in the leukocyte count, the distribution of cell types is altered
significantly during pregnancy. Specifically, during the third trimester, the percentages of
granulocytes and CD8 T lymphocytes are significantly increased, along with a concomitant
reduction in the percentages of CD4 T lymphocytes and monocytes. Moreover, circulating
leukocytes undergo significant phenotypic changes including, for example, the upregulation
of certain adhesion molecules (Luppi, 2002).
Inflammatory Markers
Many tests performed to diagnose inflammation cannot be used reliably during pregnancy.
For example, leukocyte alkaline phosphatase levels are used to evaluate myeloproliferative
disorders and are increased beginning early in pregnancy. The concentration of C-reactive
protein, an acute-phase serum reactant, rises rapidly in response to tissue trauma or
inflammation. Anderson (2013), Watts (1991), and all their associates measured C-reactive
protein levels across pregnancy and found that median values were higher than for
nonpregnant women. In the latter study, levels were also found to be elevated further during
labor. Of nonlaboring women, 95 percent had levels of 1.5 mg/dL or less, and gestational age
did not affect serum levels. Another marker of inflammation, the erythrocyte sedimentation

rate (ESR), is increased in normal pregnancy because of elevated plasma globulins and
fibrinogen (Hytten, 1971).
Complement factors C3 and C4 also are significantly elevated during the second and third
trimesters (Gallery, 1981; Richani, 2005). Last, levels of procalcitonin, a normal precursor of
calcitonin, increase at the end of the third trimester and through the first few postpartum days
(p. 70). Procalcitonin levels are elevated in severe bacterial infections but remain low in viral
infections and nonspecific inflammatory disease. Based on their longitudinal study, Paccolat
and colleagues (2011) concluded that a threshold of 0.25 g/L can be used during the third
trimester and peripartum to exclude infection.
Coagulation and Fibrinolysis
During normal pregnancy, both coagulation and fibrinolysis are augmented but remain
balanced to maintain hemostasis (Appendix, p. 1288). They are even more enhanced in
multifetal gestation (Morikawa, 2006). Evidence of activation includes increased
concentrations of all clotting factors except factors XI and XIII (Table 4-3). The clotting time
of whole blood, however, does not differ significantly in normal pregnant women.
Considering the substantive physiological increase in plasma volume in normal pregnancy,
such increased concentrations represent a markedly augmented production of these
procoagulants (Kenny, 2014). In a longitudinal study of 20 healthy nulligravid women, for
example, McLean and coworkers (2012) demonstrated progressive increases in the level and
rate of thrombin generation throughout gestation. These returned to preconceptional levels by
1 year after pregnancy. In normal nonpregnant women, plasma fibrinogen (factor I) averages
300 mg/dL and ranges from 200 to 400 mg/dL. During normal pregnancy, fibrinogen
concentration increases approximately 50 percent. In late pregnancy, it averages 450 mg/dL,
with a range from 300 to 600 mg/dL. The percentage of highmolecular- weight fibrinogen is
unchanged (Manten, 2004). This contributes greatly to the striking increase in the erythrocyte
sedimentation rate as discussed previously. Some of the pregnancy-induced changes in the
levels of coagulation factors can be duplicated by the administration of estrogen plus
progestin contraceptive tablets to nonpregnant women. The end product of the coagulation
cascade is fibrin formation, and the main function of the fibrinolytic system is toremove
excess fibrin. Tissue plasminogen activator (tPA) converts plasminogen into plasmin, which
causes fibrinolysis and produces fibrin-degradation products such as d-dimers. Studies of the
fibrinolytic system in pregnancy have produced conflicting results, but most evidence
suggests that fibrinolytic activity is actually reduced in normal pregnancy (Kenny, 2014). For
example, tPA activity gradually decreases during normal pregnancy. Moreover, plasminogen

activator inhibitor type 1 (PAI-1) and type 2 (PAI-2), which inhibit tPA and regulate fibrin
degradation by plasmin, increase during normal pregnancy (Hui, 2012; Robb, 2009). As
reviewed by Holmes and Wallace (2005), these changeswhich may indicate that the
fibrinolytic system is impairedare countered by increased levels of plasminogen and
decreased levels of another plasmin inhibitor, 2 antiplasmin. Such changes serve to ensure
hemostatic balance during normal pregnancy.
Platelets
Normal pregnancy also involves platelet changes. In a study ofalmost 7000 healthy women at
term, Boehlen and colleagues (2000) found that the average platelet count was decreased
slightly during pregnancy to 213,000/L compared with 250,000/L in nonpregnant control
women. Thrombocytopenia defined as below the 2.5th percentile corresponded to a platelet
count of 116,000/L. Decreased platelet concentrations are partially due
to hemodilutional effects. There likely also is increased platelet consumption, leading to a
greater proportion of younger and therefore larger platelets (Valera, 2010). Further supporting
this concept, Hayashi and associates (2002) found that beginning in midpregnancy,
production of thromboxane A2, which induces platelet aggregation, progressively increases.
Because of splenicenlargement, there may also be an element of hypersplenism (Kenny,
2014).
Regulatory Proteins
There are several natural inhibitors of coagulation, including proteins C and S and
antithrombin. Inherited or acquired deficiencies of these and other natural regulatory proteins
collectively referred to as thrombophiliasaccount for many thromboembolic episodes
during pregnancy. They are discussed in detail in Chapter 52 (p. 1029).Activated protein C,
along with the cofactors protein S and factor V, functions as an anticoagulant by neutralizing
the procoagulants factor Va and factor VIIIa (Fig. 521, p. 1030). During pregnancy,
resistance to activated protein C increases progressively and is related to a concomitant
decrease in free protein S and increase in factor VIII levels. Between the first and third
trimesters, activated protein C levels decrease from 2.4 to 1.9 U/mL, and free protein S
concentrations decline from 0.4 to 0.16 U/mL (Walker, 1997). Oral contraceptivesalso
decrease free protein S levels. Levels of antithrombin remain relatively constant throughout
gestation and the early puerpe2007). Moreover, in a study of 77 recently delivered gravidas,
Gayer and coworkers (2012) found that splenic size was 68-percent larger compared with that
of nonpregnant controls.

The cause of this splenomegaly is unknown, but it might follow the increased blood volume
and/or the hemodynamic changes of pregnancy, which are subsequently discussed.
Sonographically, the echogenic appearance of the spleen remains homogeneous throughout
gestation.
CARDIOVASCULAR SYSTEM
During pregnancy and the puerperium, the heart and circulation undergo remarkable
physiological adaptations. Changes in cardiac function become apparent during the first 8
weeks of pregnancy (Hibbard, 2014). Cardiac output is increased as early as the fifth week
and reflects a reduced systemic vascular resistance and an increased heart rate. Compared
with prepregnancy measurements, brachial systolic blood pressure, diastolic blood pressure,
and central systolic blood pressure are all significantly lower 6 to 7 weeks from the last
menstrual period (Mahendru, 2012). The resting pulse rate increases approximately 10
beats/min during pregnancy. Between weeks 10 and 20, plasma volume expansion begins,
and preload is increased. Ventricular performance during pregnancy is influenced by both the
decrease in systemic vascular resistance and changes in
pulsatile arterial flow. Multiple factors contribute to this overall altered hemodynamic
function, which allows the physiologicaldemands of the fetus to be met while maintaining
maternal cardiovascular integrity (Hibbard, 2014). These changes during the last half of
pregnancy are graphically summarized in Figure 4-7. The important effects of maternal
posture on hemodynamics are also illustrated.
Heart
As the diaphragm becomes progressively elevated, the heart is displaced to the left and
upward and is rotated on its long axis. As a result, the apex is moved somewhat laterally from
its usual position and produces a larger cardiac silhouette in chest radiographs (Fig. 4-8).
Furthermore, pregnant women normally have some degree of benign pericardial effusion,
which may increase the cardiac silhouette (Enein, 1987). Variability of these factors makes it
difficult to precisely identify moderate degrees of cardiomegaly by simple radiographic
studies. Normal pregnancy induces no characteristic electrocardiographic changes other than
slight left-axis deviation due to the altered heart position. Many of the normal cardiac sounds
are modified during pregnancy. Cutforth and MacDonald (1966) used phonocardiography and
documented: (1) an exaggerated splitting of the first heart sound and increased loudness of
both components, (2) no definite changes in the aortic and pulmonary elements of the second
sound, and (3) a loud, easily heard third sound (Fig. 49-2, p. 975). In 90 percent of pregnant
women, they also heard a systolic murmur that was intensified during inspiration in some or

expiration in others and that disappeared shortly after delivery. A soft diastolic murmur was
noted transiently in 20 percent, and continuous murmurs arising from the breast vasculature
in 10 percent. Structurally, the increasing plasma volume seen during normal pregnancy is
reflected by enlarging cardiac end-systolic and end-diastolic dimensions. At the same time,
however, there is no change in septal thickness or in ejection fraction. This is because the
dimensional changes are accompanied by substantive ventricular remodeling, which is
characterized by eccentric left-ventricular mass expansion averaging 30 to 35 percent near
term. In the nonpregnant state, the heart is capable of remodeling in response to stimuli such
as hypertension and exercise. Such cardiac plasticity likely is a continuum that encompasses
physiological growth, such as that in exercise, as well as pathological hypertrophysuch as
with hypertension (Hill, 2008). And although it is widely held that there is physiological
hypertrophy of cardiac myocytes as a result of pregnancy, this has never been absolutely
proven. Hibbard and colleagues (2014) concluded that any increased mass does not meet
criteria for hypertrophy. Certainly for clinical purposes, ventricular function during
pregnancy is normal, as estimated by the Braunwald ventricular function graph depicted in
Figure 4-9. For the given filling pressures, there is appropriate cardiac output so that cardiac
function during pregnancy is eudynamic. Despite these findings, it remains controversial
whether myocardial function per se is normal, enhanced, or depressed. In nonpregnant
subjects with a normal heart who sustain a high-output state, the left ventricle undergoes
longitudinal remodeling,and echocardiographic functional indices of its deformation provide
normal values. In pregnancy, there instead appears to be spherical remodeling, and these
calculated indices that measure longitudinal deformation are depressed (Savu, 2012). Thus,
these normal indices are likely inaccurate when used to assess function in pregnant women
because they do not account for the spherical eccentric hypertrophy characteristic of normal
pregnancy.
Cardiac Output
During normal pregnancy, mean arterial pressure and vascular resistance decrease, while
blood volume and basal metabolic rate increase. As a result, cardiac output at rest, when
measured in the lateral recumbent position, increases significantly beginning in early
pregnancy (Duvekot, 1993; Mabie, 1994). It continues to increase and remains elevated
during the remainder of pregnancy (Fig. 4-10). During late pregnancy in a supine woman, the
large uterus rather consistently compresses venous return from the lower body. It also may
compress the aorta (Bieniarz, 1968). In response, cardiac filling may be reduced and cardiac
output diminished. Specifically, Bamber and Dresner (2003) found cardiac output at term to

increase 1.2 L/minalmost 20 percentwhen a woman was moved from her back onto her
left side. Moreover, in the supine pregnant woman, uterine blood flow estimated by Doppler
velocimetry decreases by a third (Jeffreys, 2006). Of note, Simpson and James (2005) found
that fetal oxygen saturation is approximately 10 percent higher if a laboring woman is in a
lateral recumbent position compared with supine. Upon standing, cardiac output falls to the
same degree as
in the nonpregnant woman (Easterling, 1988).
In multifetal pregnancies, compared with singletons, maternal cardiac output is augmented
further by almost another 20 percent because of a greater stroke volume (15 percent) and
heart rate (3.5 percent). Left atrial diameter and left ventricular end-diastolic diameter are
also increased due to augmented preload (Kametas, 2003b). The increased heart rate and
inotropic contractility imply that cardiovascular reserve is reduced in multifetal gestations.
During the first stage of labor, cardiac output increases moderately. During the second stage,
with vigorous expulsive efforts, it is appreciably greater (see Fig. 4-10). The
pregnancyinduced increase is lost after delivery, at times dependent on blood loss.
Hemodynamic Function in Late Pregnancy
To further elucidate the net changes of normal pregnancyinduced cardiovascular changes,
Clark and associates (1989) conducted invasive studies to measure hemodynamic function
late in pregnancy (Table 4-4). Right heart catheterization was performed in 10 healthy
nulliparous women at 35 to 38 weeks, and again at 11 to 13 weeks postpartum. Late
pregnancy was associated with the expected increases in heart rate, stroke volume, and
cardiac output. Systemic vascular and pulmonary vascular resistance both decreased
significantly, as did colloid osmotic pressure. Pulmonary capillary wedge pressure and central
venous pressure did not change appreciably between late pregnancy and the puerperium.
Thus, as shown earlier in Figure 4-9, although cardiac output is increased, left ventricular
function as measured bystroke work index remains similar to the nonpregnant normal range.
Put another way, normal pregnancy is not a continuous high-output state.
Circulation and Blood Pressure
Changes in posture affect arterial blood pressure. Brachial artery pressure when sitting is
lower than that when in the lateral recumbent supine position (Bamber, 2003). Arterial
pressure usually decreases to a nadir at 24 to 26 weeks and rises thereafter. Diastolic pressure
decreases more than systolic (Fig. 4-11). Antecubital venous pressure remains unchanged
during pregnancy. In the supine position, however, femoral venous pressure rises steadily,

from approximately 8 mm Hg early in pregnancy to 24 mm Hg at term. Wright and

coworkers (1950) demonstrated that venous blood flow in the legs is retarded during
pregnancy except when the lateral recumbent position is assumed. This tendency toward
blood stagnation in the lower extremities during latter pregnancy is attributable to occlusion
of the pelvic veins and inferior vena cava by the enlarged uterus. The elevated venous
pressure returns to normal when the pregnant woman lies on her side and immediately after
delivery (McLennan, 1943). These alterations contribute to the dependent edema frequently
experienced and to the development of varicose veins in the legs and vulva, as well as
hemorrhoids. These changes also predispose to deep-vei thrombosis (Chap. 52, p. 1035).
Supine Hypotension
In approximately 10 percent of women, supine compression of the great vessels by the uterus
causes significant arteria hypotension, sometimes referred to as the supine hypotensive
syndrome (Kinsella, 1994). Also when supine, uterine arterial pressureand thus blood flow
is significantly lower than that in the brachial artery. As discussed in Chapter 24 (p.
494),this may directly affect fetal heart rate patterns (Tams, 2007). These changes are also
seen with hemorrhage or with spinal analgesia (Chap. 25, p. 511).
Renin, Angiotensin II, and Plasma Volume
The renin-angiotensin-aldosterone axis is intimately involved in blood pressure control via
sodium and water balance. All components of this system are increased in normal pregnancy
(Bentley-Lewis, 2005). Renin is produced by both the maternal kidney and the placenta, and
increased renin substrate (angiotensinogen) is produced by both maternal and fetal liver.
Elevated angiotensinogen levels result, in part, from increased estrogen production during
normal pregnancy and are important in firsttrimester blood pressure maintenance (August,
1995). Gant and associates (1973) studied vascular reactivity to angiotensin II throughout
pregnancy. Nulliparas who remained normotensive became and stayed refractory to the
pressor effects of infused angiotensin II. Conversely, those who ultimately became
hypertensive developed, but then lost, this refractoriness. Follow-up studies by Gant (1974)
and Cunningham (1975) and their colleagues indicated that increased refractoriness to
angiotensin II stemmed from individual vessel refractoriness. Said another way, the
abnormally increased sensitivity was an alteration in vessel wall refractoriness rather than the
consequence of altered blood volume or renin-angiotensin secretion. The vascular
responsiveness to angiotensin II may be progesterone related. Normally, pregnant women
lose their acquired vascular refractoriness to angiotensin II within 15 to 30 minutes after the
placenta is delivered. Moreover, large amounts of intramuscular progesterone given during

late labor delay this diminishing refractoriness. And although exogenous progesterone does
not restore angiotensin II refractoriness to women with gestational hypertension, this can be
done with infusion of its major metabolite, 5-dihydroprogesterone.
Cardiac Natriuretic Peptides
At least two species of theseatrial natriuretic peptide (ANP) and B-type natriuretic peptide
(BNP)are secreted by cardiomyocytes in response to chamber-wall stretching. These
peptides regulate blood volume by provoking natriuresis, diuresis, and vascular smoothmuscle relaxation (Clerico, 2004). In nonpregnant and pregnant patients, levels of BNP and
of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) may be useful in screening for
depressed left ventricular systolic function and determining chronic heart failure prognosis
(Jarolim, 2006; Tanous, 2010).
During normal pregnancy, plasma ANP and BNP levels are maintained in the nonpregnant
range despite increased plasma volume (Lowe, 1992; Yurteri-Kaplan, 2012). In one study,
Resnik and coworkers (2005) found median BNP levels to be stable across pregnancy with
values < 20 pg/mL. BNP levels are increased in severe preeclampsia, and Tihtonen and
colleagues (2007) concluded that this was caused by cardiac strain from increased afterload.
It would appear that ANPinduced physiological adaptations participate in extracellular fluid
volume expansion and in the increased plasma aldosterone concentrations characteristic of
normal pregnancy. A third species, C-type natriuretic peptide (CNP), is predominantly
secreted by noncardiac tissues. Among its diverse biological functions, this peptide appears to
be a major regulatorof fetal bone growth. Walther and Stepan (2004) have provided a detailed
review of its function during pregnancy.
Prostaglandins
Increased prostaglandin production during pregnancy is thought to have a central role in
control of vascular tone, blood pressure, and sodium balance. Renal medullary prostaglandin
E2 synthesis is increased markedly during late pregnancy and is presumed to be natriuretic.
Prostacyclin (PGI2), the principal prostaglandin of endothelium, also is increased during late
pregnancy and regulates blood pressure and platelet function. It also has been implicated in
the angiotensin resistance characteristic of normal pregnancy (Friedman, 1988). The ratio of
PGI2 to thromboxane in maternal urine and blood has been considered important in
preeclampsia pathogenesis (Chap. 40, p. 735). The molecular mechanisms regulating
prostacyclin pathways during pregnancy have recently been reviewed by Majed and Khalil
(2012).
Endothelin

There are several endothelins generated in pregnancy. Endothelin-1 is a potent

vasoconstrictor produced in endothelial and vascular smooth muscle cells and regulates local
vasomotor tone (Feletou, 2006; George, 2011). Its production is stimulated by angiotensin II,
arginine vasopressin, and thrombin. Endothelins, in turn, stimulate secretion of ANP,
aldosterone, and catecholamines. As discussed in Chapter 21 (p. 427), there are endothelin
receptors in pregnant and nonpregnant myometrium. Endothelins also have been identified in
the amnion, amnionic fluid, decidua, and placenta (Kubota, 1992; Margarit, 2005). Vascular
sensitivity to endothelin-1 is not altered during normal pregnancy. Ajne and associates (2005)
postulated that vasodilating factors counterbalance
the endothelin-1 vasoconstrictor effects and reduce peripheral vascular resistance.
Nitric Oxide
This potent vasodilator is released by endothelial cells and may have important implications
for modifying vascular resistance during pregnancy. Moreover, nitric oxide is one of the most
important mediators of placental vascular tone and development (Krause, 2011; Kulandavelu,
2013).