Changes in blood and plasma volume

Among the most significant hematologic changes during pregnancy are increases in blood and plasma volume (Figure 8-1). These changes result in the hypervolemia of pregnancy, which is in turn responsible for many of the alterations in blood cellular components and plasma constituents. Circulating blood volume increases by 30% to 40% (approximately 1 ½ L), with a usual range of 30% to 45%.^{46,87,128,179} The increased blood volume is due to an increase in plasma volume that is followed by an increase in the total red blood cell (RBC) volume. Blood volume changes begin at 6 to 8 weeks, peak at 28 to 34 weeks at values about 1200 to 1600 mL higher than in nonpregnant women, then reach a plateau or decrease slightly to term.^87,128

Plasma volume increases progressively from 6 to 8 weeks by approximately 45% to 50% (range, 40% to 60%) or about 1200 to 1600 mL above nonpregnant values.^{54,87,128,158,188} Plasma volume increases rapidly during the second trimester, followed by a slower but progressive increase that reaches its maximum of 4700 to 5200 mL around 32 weeks.^87,128 The enlarged plasma volume is accommodated by the vasculature of the uterus, breasts, muscles, kidneys, and skin. The increased volume leads to hemodilution with a net decrease in RBC volume and total circulating plasma proteins.

Plasma volume, placental mass, and birth weight are positively correlated.^54,73 Fetal growth correlates more closely with maternal plasma volume increases than with changes in RBC volume. Alterations in the usual increase in plasma volume are associated with pregnancy complications. A greater than normal increase in plasma volume has been observed in multiparous women (probably related to a tendency for higher weight infants) and with maternal obesity, large for gestational age infants, prolonged pregnancy, and multiple gestation.⁵⁴

In twin pregnancies, plasma volume increases up to 70% over nonpregnant values, with further elevations seen in women with triplets and other multiple pregnancies.^38,54 The lower than expected hematocrit seen in these women may be due to hemodilution from excessive plasma volume and may not indicate a problem with erythropoiesis per se. Preeclampsia is associated with a reduction in the expected increase in plasma volume in most studies (see Chapter 9).^{6,10,29,62,100,108,128} This may be due to vasoconstriction altering the intravascular compartment or a more “leaky” vasculature.¹⁰

The etiology of plasma volume changes in pregnancy is thought to be related to the effects of nitric oxide–mediated vasodilation on the renin-angiotensin-aldosterone system and subsequent sodium and water retention (see Chapter 11).^32,128 These changes are also influenced by hormonal effects and are closely linked with the alterations seen in fluid balance and in the renal and cardiovascular systems. Hormonal influences, especially the effects of progesterone, on the vasculature of the venous system lead to decreased venous tone, increased capacity of the veins and venules, and decreased vascular resistance. These changes allow the vasculature to accommodate the increased blood volume. Estrogen and progesterone influence plasma renin activity and aldosterone levels, resulting in retention of sodium and an increase in total body water.⁷³ Most of this extra water is extracellular and available to contribute to the increased plasma volume. Changes in plasma volume have also been linked to a mechanical effect, with the low-resistance uteroplacental circulation acting as an arteriovenous shunt. This shunt provides physical space to accommodate the increased cardiac output and corresponding change in plasma volume.^38,73

Increased plasma volume and hypervolemia reduce blood viscosity. Hypervolemia also leads to hemodilution and changes in plasma protein and blood cellular components, which further reduce viscosity. Blood viscosity decreases approximately 20% during the first two trimesters. During the third trimester, viscosity may increase slightly. The decreased viscosity reduces resistance to flow and the cardiac effort needed, thus conserving maternal energy resources.³⁸

Changes in blood cellular components

The principal change in blood cellular components during pregnancy is an increase in RBC volume (Table 8-2). This alteration, in conjunction with changes in plasma volume, is reflected in changes in the hemoglobin and hematocrit.

Changes in red blood cells.

The total RBC volume increases by 20% to 30% (250 to 450 mL) during pregnancy.^54,128,158 Changes in RBC volume are due to increased circulating erythropoietin (Epo), which stimulates erythropoiesis and accelerated RBC production. The rise in Epo in the last two trimesters is due to progesterone, possibly prolactin, and human placental lactogen rather than to a decrease in oxygen-carrying capacity, which is the usual stimulus for Epo production.^54,128 The magnitude of change in RBC volume varies and is influenced by the woman’s iron stores.³⁸ The increase in RBCs reflects the increase in oxygen demands (which rise 15%) during pregnancy.^178,179 

The increase in erythropoiesis and total RBC volume begins during the first trimester.^54,87 The increase occurs at a relatively constant rate, but slower than changes in plasma volume, and may accelerate slightly during the third trimester.^54,73 Hemodilution is maximal at 28 to 34 weeks and leads to a lower hemoglobin, hematocrit and RBC count.⁸⁷ The increased RBC production results in a moderate erythroid hyperplasia of the bone marrow and an increase in the reticulocyte count.

RBC 2,3-diphosphoglycerate (2,3-DPG) rises beginning early in pregnancy and leads to a gradual shift to the right of the maternal oxygen-hemoglobin dissociation curve (see Chapter 10). This reduces the affinity of maternal hemoglobin for oxygen (see box on p. 301) and favors release of oxygen in the peripheral tissues, including the intervillous space, which facilitates oxygen transfer from mother to fetus and fetal growth.^54,73,128 Alterations in placental function that occur with maternal disorders such as preeclampsia, chronic renal disease, diabetes, and severe anemia can decrease oxygen transfer across the placenta. The fetus may develop chronic hypoxia, with stimulation of erythropoietin (Epo) production, increased erythropoiesis, polycythemia, and increased neonatal morbidity.

The mean cell diameter and thickness of the RBCs also change, resulting in a cell that is more spherical in shape. Because the increase in plasma volume is three times greater than the RBC volume increase, the net result is a decrease in the total RBC count, hemoglobin, and hematocrit (see Table 8-2). Changes in the mean corpuscular volume (MCV) and mean corpuscular hemoglobin volume (MCHV) are related to iron status. In women with adequate iron, the MCV and MCHV are relatively stable; in iron-deficient women, these values may decrease.^87,179

The hemoglobin and hematocrit decrease from the second trimester on as plasma volume peaks. Thus although total body hemoglobin increases 85 to 150 g in pregnancy, net hemoglobin decreases. Even with adequate iron supplementation, the hemoglobin decreases about 2 g/dL (20 g/L) to a mean of about 11.6 g/dL (116 g/L) in the second trimester as a result of hemodilution.⁷⁴ At term the hemoglobin averages 12.1 to 12.5 g/dL (121 to 125 g/L), with a range of 11 to 13 g/dL (110 to 130 g/L) versus a mean of 14 ± 2 (140 ± 20 g/L) for nonpregnant females. The Centers for Disease Control and Prevention (CDC) suggests values of 11 g/dL (110 g/L) (first and second trimesters) and 10.5 g/dL (105 g/L) (third trimester) as the lowest acceptable values for screening pregnant women.^36,54 The mean hematocrit is 33.8% (range, 33% to 39%) at term.^54,87 The fall in the hematocrit may help protect the woman from thromboembolism by decreasing blood viscosity and enhancing perfusion.¹²⁸ A high hematocrit in a pregnant woman may indicate a low plasma volume and a relative hypovolemia. Changes in the hemoglobin and hematocrit in pregnant women are illustrated in Figure 8-2.

Changes in plasma components

Many components of plasma—including plasma proteins, electrolytes, serum iron, lipids, and enzymes—change during pregnancy (Table 8-3). Total plasma proteins decrease 10% to 14%, with much of the change occurring in the first trimester. Although there is an absolute increase in albumin concentration during the first trimester, there is a relative decrease due to increased blood volume and hemodilution. Decreased albumin leads to a net decrease in colloid osmotic (oncotic) pressure, reducing the normal forces counteracting edema formation. Although edema formation in pregnancy is primarily due to alterations in venous hydrostatic pressure, decreased oncotic pressure from the relative decrease in albumin is an important contributory factor.¹⁵ 

Globulin concentration demonstrates both absolute and relative increases, leading to progressive falls in the albumin-to-globulin ratio. Both α- and β-globulin increase progressively during pregnancy; γ-globulin decreases slightly. Fibrinogen also demonstrates both absolute and relative increases of 50% to 80%.^15,46 The erythrocyte sedimentation rate (ESR) increases progressively during pregnancy, probably due to the elevation in plasma globulin and fibrinogen levels. Alterations in other plasma proteins are summarized in Table 8-3.

The alterations in plasma proteins alter protein binding of substances such as calcium, drugs, and anesthetic agents. Because many drugs are transported in the blood bound to albumin, doses of some drugs may need to be altered during pregnancy (see Chapter 7). Increased binding of substances such as calcium reduces the level of free calcium in the maternal plasma. As a result, calcium must be actively transported across the placenta to the fetus (see Chapter 17).

Decreases in serum electrolytes (anions, cations, and buffer base) reduce plasma osmolarity by 8 to 10 mOsm/L during the first trimester.¹⁵ These changes are due to both hypervolemia and the effects of respiratory system alterations, particularly hyperventilation with increased CO₂ loss (see Chapter 10).³⁸

Serum iron decreases during pregnancy, especially after 28 weeks and in women without adequate iron stores. Iron needs during pregnancy are summarized in Table 8-4. Serum ferritin is a more precise indicator of reticuloendothelial iron stores. 1 mcg/L (2.5 pmol/L) serum ferritin is equal to 8 mg of stored iron in the adult. Serum ferritin levels in pregnancy are 15 to 150 ng/mL (33.7 to 337 pmol/L).⁵⁴ In women without adequate iron, serum ferritin levels fall until 30 to 32 weeks and then stabilize. The greatest decrease in serum ferritin is between 12 and 25 weeks due to the rapid expansion of maternal RBC volume during this time (see Figure 8-2).¹⁸⁹ With adequate iron, serum ferritin levels stabilize by 28 weeks or slightly earlier, and may even rise near term.^15,54 Decreases in serum ferritin in early pregnancy are due to mobilization of iron stores for maternal hemoglobin synthesis; later decreases are due to increased fetal iron uptake. In multiparous women the decrease in serum ferritin occurs earlier and may be greater.

Levels of serum lipids rise with marked elevations in cholesterol and phospholipids. Cholesterol is an essential precursor for steroid hormone production by the placenta; phospholipids are major components of cell membranes. The rise in serum lipids begins in the first trimester, increasing to 40% to 60% at term (see Table 8-3). Increases in serum alkaline phosphatase are due to increased placental production. As a result, alkaline phosphatase levels are not useful in evaluating liver disorders during pregnancy. Serum cholinesterase activity decreases by 30%. Increased cholinesterase activity may lead to longer periods of paralysis if substances such as succinylcholine are used during surgical procedures.¹⁵

Changes on coagulation factors and hemostasis

Pregnancy has been called an acquired hypercoagulable state, reflecting an increased risk for thrombosis and consumptive coagulopathies such as disseminated intravascular coagulation (DIC). Pregnancy is associated with increased clotting potential, decreased anticoagulants, and decreased fibrinolysis.^7,103 Hemostatic changes during pregnancy are thought to result in an ongoing low-grade activation of the coagulation system in the uteroplacental circulation, beginning as early as 11 to 15 weeks. This state of compensated intravascular coagulation is characterized by thrombin formation and local consumption of clotting factors in which component synthesis equals or exceeds consumption.^69,169 Figures 8-3 to 8-5 summarize coagulation and fibrinolysis.

Intravascular and extravascular fibrin deposits are found in the uteroplacental circulation, intervillous spaces, and placental bed. Tissue factor is found in amniotic fluid, placenta, decidua, and endometrial stroma.^93,103 Tissue factor (previously called thromboplastin) may play a nonhemostatic role in angiogenesis, cell signaling and embryogenesis.⁶³ Circulating high-molecular-weight, soluble fibrin-fibrinogen complexes—which are indicative of uteroplacental fibrin formation—also increase. During pregnancy, smooth muscle and elastic tissue within the uterine spiral arteries are replaced by a fibrin matrix (see Chapter 3). These changes allow for expansion of the vessels to accommodate increased blood flow to the placenta and to facilitate collapse of the terminal portion of the vessel with placental separation.^{69,129,133,178} Elevated levels of plasminogen-activated inhibitors may assist with the deposition of fibrin in the maternal blood vessels.⁶⁵ Increased fibrinogen, thrombin generation, and inhibition of fibrinolysis during pregnancy may interact to ensure integrity of uteroplacental vessels.¹⁰³ During late pregnancy, accumulation of mural thrombi in the vessel walls decreases the diameter of the lumen, reducing blood flow, which may result in the placental infarcts and small areas of ischemia often seen at term.

Alterations are seen in coagulation (procoagulant) factors, coagulation inhibitors, and fibrinolysis. Contact factors involved in initiation of the clotting cascade and many coagulation factors are elevated in pregnancy.^69,103,129 Factors I (fibrinogen), VII, VIII, IX, XII, and X; as well as von Willebrand factor (vWF), which is important in platelet adhesion, are markedly increased.^{26,42,71,103,129,179} Factors II and V are generally unchanged.¹⁰³ Factor XIII increases initially then decreases to about 50% of nonpregnant values in late pregnancy.^26,65 Factor XI decreases to term.¹⁰³ These changes increase thrombin generating potential.¹⁰³ A concurrent increase in fibrinogen and decrease in factor XIII (fibrin stabilizing factor) alters the process of clot stabilization and subsequent lysis during pregnancy.⁶⁹ Thrombin-antithrombin complexes double by the third trimester, indicating increased thrombin generation.^26,133

Changes in coagulation factors during pregnancy are reflected in the activated partial thromboplastin time (aPTT) and prothrombin time (PT), which decrease slightly from midpregnancy to term.²⁶ D-dimer concentrations increase progressively, which is consistent with the hypercoagulable state of pregnancy.^42,133 Bleeding times are normally unchanged.⁷¹

Coagulation inhibitors form an endogenous anticoagulant system that inhibits hemostasis (see Figure 8-4). Absolute levels of antithrombin are generally unchanged during pregnancy or may be slightly decreased by term.⁷¹ Both free and total protein are decreased.^103,128 Free protein S decreases by 60% to 70%, with the lowest levels seen at delivery.¹⁰³ This decrease is due to an increase in its carrier protein (complement 4β-binding protein).¹⁰³